Редактирование: APP (раздел)

==Publications==

{{medline-entry
|title=Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32917871
|abstract=Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein ([[APP]] ) J20 and wild-type mice with VX-765 delays both [[APP]] - and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Behavior, Animal
* Cognitive Dysfunction
* Cytokines
* Dipeptides
* Disease Models, Animal
* Encephalitis
* Female
* Humans
* Inflammation
* Male
* Memory Disorders
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Serpins
* Spatial Memory
* Viral Proteins
* para-Aminobenzoates

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486940
}}
{{medline-entry
|title=Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32660121
|abstract=The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer's disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology in vitro and in vivo. Regorafenib affected AKT signaling to attenuate lipopolysaccharide (LPS)-mediated expression of proinflammatory cytokines in BV2 microglial cells and primary cultured microglia and astrocytes. In addition, regorafenib suppressed LPS-induced neuroinflammatory responses in LPS-injected wild-type mice. In 5x FAD mice (a mouse model of AD), regorafenib ameliorated AD pathology, as evidenced by increased dendritic spine density and decreased Aβ plaque levels, by modulating [[APP]] processing and [[APP]] processing-associated proteins. Furthermore, regorafenib-injected 5x FAD mice displayed significantly reduced tau phosphorylation at T212 and S214 (AT100) due to the downregulation of glycogen synthase kinase-3 beta (GSK3β) activity. Taken together, our results indicate that regorafenib has beneficial effects on neuroinflammation, AD pathology, and dendritic spine formation in vitro and in vivo.

|keywords=* aging
* amyloid beta
* dendritic spine
* neuroinflammation
* regorafenib
* tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408082
}}
{{medline-entry
|title=An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer's disease pathogenesis: The role of [[APP]] homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32588983
|abstract=To reassess the role of amyloid beta (Aβ) and the amyloid precursor protein ([[APP]]) system in the pathogenesis of Alzheimer's disease (AD). [[APP]] is a cell adhesion molecule that has been highly conserved over the course of phylogeny that has critical roles in brain development, synaptic plasticity, and the brain's intrinsic immune system. The amyloid cascade hypothesis describes a relatively linear, deterministic sequence of events triggered by a gain of Aβ peptide fragment toxicity that results in neurodegeneration and cognitive loss, yet well designed immunotherapy and beta secretase inhibitor trials that have successfully targeted Aβ have failed to have any consistent effects on the steady decline of cognition. Mutations of the [[APP]] and presenilin genes not only alter the ratio of longer to shorter Aβ fragments (resulting in a gain of Aβ toxicity), but also disrupt the normal homeostatic roles of their respective proteins. The evolutionary history, physiological importance, and complexity of the [[APP]] and presenilin systems, as well as other critical components including tau and apolipoprotein E (APOE) imply that altered function of such systems could have severe consequences that include but need not be limited to a gain of Aβ toxicity and would more generally result in altered homeostasis of [[APP]]-related functions. Challenges that a loss of [[APP]] homeostasis addresses better than the more limited gain of Aβ toxicity model include the topographic mismatches between Aβ and tau pathology, the profile and chronology of cognitive and biomarker changes that precede the clinical expression of mild cognitive impairment and dementia, and the disappointments of Aβ targeted therapeutics among others. The importance of [[APP]], α- and β-secretases, the presenilins and γ-secretase, as well as tau was recognized by the authors of the amyloid cascade hypothesis, and has since led multiple investigators to propose alternative, more balanced hypotheses including reduced homeostasis and frank loss-of-function of key components that include but go beyond the currently envisioned linear model of Aβ toxicity.

|keywords=* aging
* amyloid hypothesis
* amyloid precursor protein homeostasis
* late onset Alzheimer's disease
* young onset Alzheimer's disease
|full-text-url=https://sci-hub.do/10.1002/alz.12124
}}
{{medline-entry
|title=Transcriptomic profiling of microglia and astrocytes throughout aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32238175
|abstract=Activation of microglia and astrocytes, a prominent hallmark of both aging and Alzheimer's disease (AD), has been suggested to contribute to aging and AD progression, but the underlying cellular and molecular mechanisms are largely unknown. We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and [[APP]]-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles. Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). And most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes. Overall, our RNA-seq data provide a valuable resource for future investigations into the roles of microglia and astrocytes in aging- and amyloid-β-induced AD pathologies.

|keywords=* Aging
* Alzheimer’s disease (AD)
* Astrocyte
* Microglia
* RNA-seq
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115095
}}
{{medline-entry
|title=Platelets in Amyloidogenic Mice Are Activated and Invade the Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32194368
|abstract=Alzheimer's disease (AD) is a neurodegenerative disease with a complex and not fully understood pathogenesis. Besides brain-intrinsic hallmarks such as abnormal deposition of harmful proteins, i.e., amyloid beta in plaques and hyperphosphorylated Tau in neurofibrillary tangles, blood-derived elements, in particular, platelets have been discussed to be involved in AD pathogenesis. The underlying mechanisms, however, are rather unexplored. Here, we investigate a potential role of platelets in an AD transgenic animal model with severe amyloid plaque formation, the [[APP]]-PS1 transgenic mice, and analyzed the presence, spatial location and activation status of platelets within the brain. In [[APP]]-PS1 mice, a higher number of platelets were located within the brain parenchyma, i.e., outside the cerebral blood vessels compared to WT controls. Such platelets were activated according to the expression of the platelet activation marker CD62P and to morphological hallmarks such as membrane protrusions. In the brain, platelets were in close contact exclusively with astrocytes suggesting an interaction between these two cell types. In the bloodstream, although the percentage of activated platelets did not differ between transgenic and age-matched control animals, [[APP]]-PS1 blood-derived platelets showed remarkable ultrastructural peculiarities in platelet-specific organelles such as the open canalicular system (OCS). This work urges for further investigations on platelets and their yet unknown functional roles in the brain, which might go beyond AD pathogenesis and be relevant for various age-related neurodegenerative diseases.

|keywords=* Alzheimer’s disease
* aging
* astrocytes
* platelets
* vascular pathology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063083
}}
{{medline-entry
|title=Disruption of synaptic expression pattern and age-related DNA oxidation in a neuronal model of lead-induced toxicity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32058320
|abstract=Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (pro[[BDNF]]) increased, while that of mature [[BDNF]] (m[[BDNF]]), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of [[BACE1]] protein and tau phosphorylation level in PFC and hippocampus increased, [[APP]] mRNAs in PFC and prolonged induction of [[BACE1]] in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.

|keywords=* Aging mice
* Brain-derived neurotrophic factor precursor
* Latent expression pattern
* Lead
* Pubertal exposure
* Synaptic deficits
* Tau phosphorylation
|full-text-url=https://sci-hub.do/10.1016/j.etap.2020.103350
}}
{{medline-entry
|title=CHIP modulates [[APP]]-induced autophagy-dependent pathological symptoms in Drosophila.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31777182
|abstract=Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full-length human [[APP]] in Drosophila and established a fly AD model that exhibits multiple AD-like symptoms. Here we report that depletion of CHIP effectively palliated [[APP]]-induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for [[APP]]-induced autophagy dysfunction, which promotes Aβ production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal [[APP]] activity, but also contributes to dysregulated [[APP]] metabolism and subsequent AD pathogenesis.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Autophagy
* Brain
* Cognitive Dysfunction
* Disease Models, Animal
* Dopaminergic Neurons
* Down-Regulation
* Drosophila
* Drosophila Proteins
* Eye
* Learning Disabilities
* Locomotion
* Longevity
* Nuclear Proteins
* Presenilins
* RNA Interference
* Wings, Animal
|keywords=* 
CHIP

* APP
* Alzheimer’s disease
* Aβ
* autophagy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996943
}}
{{medline-entry
|title=Studies on [[APP]] metabolism related to age-associated mitochondrial dysfunction in [[APP]]/PS1 transgenic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31744937
|abstract=The aging brain with mitochondrial dysfunction and a reduced adenosine 5'-triphosphate (ATP) has been implicated in the onset and progression of β-Amyloid (Aβ)-induced neuronal toxicity in AD. To unravel the function of ATP and the underlying mechanisms on AD development, [[APP]]/PS1 double transgenic mice and wild-type (WT) C57 mice at 6 and 10 months of age were studied. We demonstrated a decreased ATP release in the hippocampus and platelet of [[APP]]/PS1 mice, comparing to C57 mice at a relatively early age. Levels of Aβ were raised in both hippocampus and platelet of [[APP]]/PS1 mice, accompanied by a decrease of α-secretase activity and an increase of β-secretase activity. Moreover, our results presented an age-dependent rise in mitochondrial vulnerability to oxidation in [[APP]]/PS1 mice. In addition, we found decreased pSer473-Akt levels, increased GSK3β activity by inhibiting phosphorylation at Ser9 in aged [[APP]]/PS1 mice and these dysfunctions probably due to down-regulation of Bcl-2 and up-regulation of cleaved caspase-3. Therefore, we demonstrate that PI3K/Akt/GSK3β signaling pathway could be involved in Aβ-associated mitochondrial dysfunction of [[APP]]/PS1 mice and [[APP]] abnormal metabolism in platelet might provide potential biomarkers for early diagnosis of AD.
|mesh-terms=* Adenosine Triphosphate
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Blood Platelets
* Disease Models, Animal
* Hippocampus
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria
* Presenilin-1
|keywords=* APP/PS1 mice
* Amyloid-beta
* adenosine 5’-triphosphate
* mitochondria dysfunction
* platelets
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914425
}}
{{medline-entry
|title=Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31733664
|abstract=Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins [[MAPT]] (Tau), amyloid beta precursor protein ([[APP]]), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, [[HK1]], [[AK1]], [[PGAM1]], CKB), cytoskeletal development (BASP1, [[CAP1]], [[DPYSL2]] [CRMP2], [[ALDOA]], [[TUBA1A]], [[CFL2]], ACTG1), cellular/oxidative stress (HSPA5, [[HSPA8]], [[ENO1]], ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human [[MAPT]], [[APP]], and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, [[IRS1]], [[IGF1R]], [[PTEN]], ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
|mesh-terms=* Alcohol Drinking
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Behavior, Animal
* Brain
* Disease Models, Animal
* Mice, Transgenic
* tau Proteins
|keywords=* Aging
* Amyloid beta
* Ethanol
* GSK
* Immunohistochemistry
* Morris Water Maze
* Prepulse inhibition
* Self-administration
* Tau pathology
* Transgenic mouse model
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939615
}}
{{medline-entry
|title=Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31673052
|abstract=Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical [[MAPT]] (tau) aggregation in familial and idiopathic Alzheimer's disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic [[APP]] /PS1  mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the [[APP]] /PS1  brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [ F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, 'wild-type' tau aggregate secondarily to Aβ in [[APP]] /PS1  mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloidosis
* Animals
* Disease Models, Animal
* Mice
* Mice, Transgenic
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823454
}}
{{medline-entry
|title=Intermittent Hypoxia-Hyperoxia Training Improves Cognitive Function and Decreases Circulating Biomarkers of Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Pilot Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31671598
|abstract=Alzheimer's disease (AD) affects not only the central nervous system, but also peripheral blood cells including neutrophils and platelets, which actively participate in pathogenesis of AD through a vicious cycle between platelets aggregation and production of excessive amyloid beta (Aβ). Platelets adhesion on amyloid plaques also increases the risk of cerebral microcirculation disorders. Moreover, activated platelets release soluble adhesion molecules that cause migration, adhesion/activation of neutrophils and formation of neutrophil extracellular traps (NETs), which may damage blood brain barrier and destroy brain parenchyma. The present study examined the effects of intermittent hypoxic-hyperoxic training (IHHT) on elderly patients with mild cognitive impairment (MCI), a precursor of AD. Twenty-one participants (age 51-74 years) were divided into three groups: Healthy Control ([i]n[/i] = 7), MCI Sham ([i]n[/i] = 6), and MCI IHHT ([i]n[/i] = 8). IHHT was carried out five times per week for three weeks (total 15 sessions). Each IHHT session consisted of four cycles of 5-min hypoxia (12% F O ) and 3-min hyperoxia (33% F O ). Cognitive parameters, Aβ and amyloid precursor protein ([[APP]]) expression, microRNA 29, and long non-coding RNA in isolated platelets as well as NETs in peripheral blood were investigated. We found an initial decline in cognitive function indices in both MCI Sham and MCI IHHT groups and significant correlations between cognitive test scores and the levels of circulating biomarkers of AD. Whereas sham training led to no change in these parameters, IHHT resulted in the improvement in cognitive test scores, along with significant increase in [[APP]] ratio and decrease in Aβ expression and NETs formation one day after the end of three-week IHHT. Such effects on Aβ expression and NETs formation remained more pronounced one month after IHHT. In conclusion, our results from this pilot study suggested a potential utility of IHHT as a new non-pharmacological therapy to improve cognitive function in pre-AD patients and slow down the development of AD.
|mesh-terms=* Aged
* Alzheimer Disease
* Biomarkers
* Case-Control Studies
* Cognition
* Cognitive Dysfunction
* Female
* Humans
* Hyperoxia
* Hypoxia
* Male
* Middle Aged
* Pilot Projects
* Respiratory Therapy
* Treatment Outcome
|keywords=* Alzheimer’s disease
* adaptation
* aging
* amyloid beta
* biomarker
* cognitive function
* hyperoxia
* intermittent hypoxia
* platelets
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862463
}}
{{medline-entry
|title=The Implication of Androgens in the Presence of Protein Kinase C to Repair Alzheimer’s Disease-Induced Cognitive Dysfunction
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31677609
|abstract=Aging, as a major risk factor of memory deficiency, affects neural signaling pathways in hippocampus. In particular, age-dependent androgens deficiency causes cognitive impairments. Several enzymes like protein kinase C (PKC) are involved in memory deficiency. Indeed, PKC regulatory process mediates α-secretase activation to cleave [[APP]] in β-amyloid cascade and tau proteins phosphorylation mechanism.  Androgens and cortisol regulate PKC signaling pathways, affecting the modulation of receptor for activated C kinase 1. Mitogen-activated protein kinase/ERK signaling pathway depends on CREB activity in hippocampal neurons and is involved in regulatory processes via PKC and androgens. Therefore, testosterone and PKC contribute in the neuronal apoptosis. The present review summarizes the current status of androgens, PKC, and their influence on cognitive learning. Inconsistencies in experimental investigations related to this fundamental correlation are also discussed, with emphasis on the mentioned contributors as the probable potent candidates for learning and memory improvement.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Androgens
* Aspartic Acid Endopeptidases
* Cognition
* Cognitive Dysfunction
* Cyclic AMP Response Element-Binding Protein
* Female
* Hippocampus
* Humans
* Learning
* MAP Kinase Signaling System
* Male
* Middle Aged
* Neoplasm Proteins
* Phosphorylation
* Protein Kinase C
* Receptors for Activated C Kinase
* tau Proteins
|keywords=* Androgens
* Cognition
* Hippocampus
* Protein kinase C
* Spatial memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984714
}}
{{medline-entry
|title=Modulation of Neural and Muscular Adaptation Processes During Resistance Training by Fish Protein Ingestions in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31596471
|abstract=Assessments of both neural and muscular adaptations during interventions would provide valuable information for developing countermeasures to age-related muscle dysfunctions. We investigated the effect of fish protein ingestion on training-induced neural and muscular adaptations in older adults. Twenty older adults participated 8 weeks of isometric knee extension training intervention. The participants were divided into two groups who took fish protein (n = 10, Alaska pollack protein, [[APP]]) or casein (n = 10, CAS). Maximal muscle strength during knee extension, lower extremity muscle mass (body impedance method), and motor unit firing pattern of knee extensor muscle (high-density surface electromyography) were measured before, during, and after the intervention. Muscle strength were significantly increased in both CAS (124.7 ± 5.8%) and [[APP]] (117.1 ± 4.4%) after intervention (p < .05), but no significant differences between the groups were observed (p > .05). Significant increases in lower extremity muscle mass from 0 to 8 weeks were demonstrated only for [[APP]] (102.0 ± 3.2, p < .05). Greater changes in motor unit firing pattern following intervention were represented in CAS more than in [[APP]]. These results suggest that nutritional supplementations could modulate neural and muscular adaptations following resistance training and fish protein ingestion preferentially induces muscular adaptation without the detectable neural adaptation in older adults.

|keywords=* Aging
* Alaska pollack protein
* Motor unit identification
* Multichannel surface electromyography
* Nutritional supplementation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164534
}}
{{medline-entry
|title=Lifelong choline supplementation ameliorates Alzheimer's disease pathology and associated cognitive deficits by attenuating microglia activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31560162
|abstract=Currently, there are no effective therapies to ameliorate the pathological progression of Alzheimer's disease (AD). Evidence suggests that environmental factors may contribute to AD. Notably, dietary nutrients are suggested to play a key role in mediating mechanisms associated with brain function. Choline is a B-like vitamin nutrient found in common foods that is important in various cell functions. It serves as a methyl donor and as a precursor for production of cell membranes. Choline is also the precursor for acetylcholine, a neurotransmitter which activates the alpha7 nicotinic acetylcholine receptor (α7nAchR), and also acts as an agonist for the Sigma-1 R (σ1R). These receptors regulate CNS immune response, and their dysregulation contributes to AD pathogenesis. Here, we tested whether dietary choline supplementation throughout life reduces AD-like pathology and rescues memory deficits in the [[APP]]/PS1 mouse model of AD. We exposed female [[APP]]/PS1 and NonTg mice to either a control choline (1.1 g/kg choline chloride) or a choline-supplemented diet (5.0 g/kg choline chloride) from 2.5 to 10 months of age. Mice were tested in the Morris water maze to assess spatial memory followed by neuropathological evaluation. Lifelong choline supplementation significantly reduced amyloid-β plaque load and improved spatial memory in [[APP]]/PS1 mice. Mechanistically, these changes were linked to a decrease of the amyloidogenic processing of [[APP]], reductions in disease-associated microglial activation, and a downregulation of the α7nAch and σ1 receptors. Our results demonstrate that lifelong choline supplementation produces profound benefits and suggest that simply modifying diet throughout life may reduce AD pathology.
|mesh-terms=* Alzheimer Disease
* Animals
* Brain
* Choline
* Cognitive Dysfunction
* Dietary Supplements
* Longevity
* Maze Learning
* Mice
* Mice, Transgenic
* Microglia
* Nootropic Agents
|keywords=* APP/PS1 mice
* Alzheimer's disease
* Aβ
* Sigma-1 receptor
* alpha7 nicotinic acetylcholine receptor
* choline supplementation
* microglia activation
* spatial memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826123
}}
{{medline-entry
|title=Antipsychotic Polypharmacy in Older Adult Asian Patients With Schizophrenia: Research on Asian Psychotropic Prescription Pattern.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31480982
|abstract=Antipsychotic polypharmacy ([[APP]]) is a controversial topic in the treatment of older adults with schizophrenia. The objective of this study was to examine the use of [[APP]] in older adult Asian patients with schizophrenia and its associated demographic and clinical factors. This study was based on the fourth survey of the consortium known as the Research on Asian Psychotropic Prescription Pattern for Antipsychotics. Fifteen Asian countries/territories participated in this survey, including Bangladesh, Mainland China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, Thailand, and Vietnam. Basic demographic and clinical characteristics were collected using a standardized data collection form. Among the 879 older adults with schizophrenia included in the survey, the rate of [[APP]] was 40.5%. Multiple logistic regression analysis revealed that higher antipsychotic doses ([i]P[/i] < .001, odds ratio [OR] = 1.003, 95% confidence interval [CI]: 1.002-1.003), longer duration of illness ([i]P[/i] = .02, OR = 1.845, 95% CI: 1.087-3.132), and the prescription of anticholinergics ([i]P[/i] < .001, OR = 1.871, 95% CI: 1.329-2.635), second-generation antipsychotics ([i]P[/i] = .001, OR = 2.264, 95% CI: 1.453-3.529), and first-generation antipsychotics ([i]P[/i] < .001, OR = 3.344, 95% CI: 2.307-4.847) were significantly associated with [[APP]]. Antipsychotic polypharmacy was common in older adult Asian patients with schizophrenia. Compared to the results of previous surveys, the use of [[APP]] showed a declining trend over time. Considering the general poor health status of older patients with schizophrenia and their increased risk of drug-induced adverse events, the use of [[APP]] in this population needs careful consideration.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Antipsychotic Agents
* Asian Continental Ancestry Group
* Female
* Humans
* Male
* Middle Aged
* Polypharmacy
* Schizophrenia
|keywords=* Asian
* antipsychotic polypharmacy
* older adult patients
* schizophrenia
|full-text-url=https://sci-hub.do/10.1177/0891988719862636
}}
{{medline-entry
|title=A pleiotropic role for exosomes loaded with the amyloid β precursor protein carboxyl-terminal fragments in the brain of Down syndrome patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31479861
|abstract=Down syndrome (DS) is characterized by cognitive deficits throughout the life span and with the development of aging-dependent Alzheimer's type neuropathology, which is related to the triplication of the amyloid β precursor protein ([[APP]]) gene. A dysfunctional endosomal system in neurons is an early characteristic of DS and [[APP]] metabolites accumulate in endosomes in DS neurons. We have previously shown enhanced release of exosomes in the brain of DS patients and the mouse model of DS Ts[Rb(12.17 )]2Cje (Ts2), and by DS fibroblasts, as compared with diploid controls. Here, we demonstrate that exosome-enriched extracellular vesicles (hereafter called EVs) isolated from DS and Ts2 brains, and from the culture media of human DS fibroblasts are enriched in [[APP]] carboxyl-terminal fragments ([[APP]]-CTFs) as compared with diploid controls. Moreover, [[APP]]-CTFs levels increase in an age-dependent manner in EVs isolated from the brain of Ts2 mice. The release of [[APP]]-CTFs-enriched exosomes may have a pathogenic role by transporting [[APP]]-CTFs into naïve neurons and propagating these neurotoxic metabolites, which are also a source of amyloid β, throughout the brain, but also provides a benefit to DS neurons by shedding [[APP]]-CTFs accumulated intracellularly.
|mesh-terms=* Amyloid beta-Protein Precursor
* Brain
* Down Syndrome
* Exosomes
* Humans
|keywords=* APP
* APP-CTFs
* Aging
* Brain
* Down syndrome
* Exosomes
* Extracellular vesicles
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960325
}}
{{medline-entry
|title=Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged [[APP]] /PS1  Transgenic Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31417357
|abstract=Insulin-like growth factor-1 (IGF-1) is a pleiotropic molecule with neurotrophic and immunomodulatory functions. Knowing the capacity of chronically activated microglia to produce IGF-1 may therefore show essential to promote beneficial microglial functions in Alzheimer's disease (AD). Here, we investigated the expression of IGF-1 mRNA and IGF-1 along with the expression of tumor necrosis factor ([[TNF]]) mRNA, and the amyloid-β (Aβ) plaque load in the hippocampus of 3- to 24-month-old [[APP]] /PS1  transgenic (Tg) and wild-type (WT) mice. As IGF-1, in particular, is implicated in neurogenesis we also monitored the proliferation of cells in the subgranular zone (sgz) of the dentate gyrus. We found that the Aβ plaque load reached its maximum in aged 21- and 24-month-old [[APP]] /PS1  Tg mice, and that microglial reactivity and hippocampal IGF-1 and [[TNF]] mRNA levels were significantly elevated in aged [[APP]] /PS1  Tg mice. The sgz cell proliferation decreased with age, regardless of genotype and increased IGF-1/[[TNF]] mRNA levels. Interestingly, IGF-1 mRNA was expressed in subsets of sgz cells, likely neuroblasts, and neurons in both genotypes, regardless of age, as well as in glial-like cells. By double [i]in situ[/i] hybridization these were shown to be [[IGF1]] mRNA  CD11b mRNA  cells, i.e., IGF-1 mRNA-expressing microglia. Quantification showed a 2-fold increase in the number of microglia and IGF-1 mRNA-expressing microglia in the molecular layer of the dentate gyrus in aged [[APP]] /PS1  Tg mice. Double-immunofluorescence showed that IGF-1 was expressed in a subset of Aβ plaque-associated CD11b  microglia and in several subsets of neurons. Exposure of primary murine microglia and BV2 cells to Aβ  did not affect IGF-1 mRNA expression. IGF-1 mRNA levels remained constant in WT mice with aging, unlike [[TNF]] mRNA levels which increased with aging. In conclusion, our results suggest that the increased IGF-1 mRNA levels can be ascribed to a larger number of IGF-1 mRNA-expressing microglia in the aged [[APP]] /PS1  Tg mice. The finding that subsets of microglia retain the capacity to express IGF-1 mRNA and IGF-1 in the aged [[APP]] /PS1  Tg mice is encouraging, considering the beneficial therapeutic potential of modulating microglial production of IGF-1 in AD.

|keywords=* aging
* cerebral amyloidosis
* insulin-like growth factor
* neurogenesis
* neuroinflammation
* tumor necrosis factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682662
}}
{{medline-entry
|title=Systems biology and network pharmacology of frailty reveal novel epigenetic targets and mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31332237
|abstract=Frailty is an age-associated condition, characterized by an inappropriate response to stress that results in a higher frequency of adverse outcomes (e.g., mortality, institutionalization and disability). Some light has been shed over its genetic background, but this is still a matter of debate. In the present study, we used network biology to analyze the interactome of frailty-related genes at different levels to relate them with pathways, clinical deficits and drugs with potential therapeutic implications. Significant pathways involved in frailty: apoptosis, proteolysis, muscle proliferation, and inflammation; genes as [[FN1]], [[APP]], [[CREBBP]], [[EGFR]] playing a role as hubs and bottlenecks in the interactome network and epigenetic factors as HIST1H3 cluster and miR200 family were also involved. When connecting clinical deficits and genes, we identified five clusters that give insights into the biology of frailty: cancer, glucocorticoid receptor, [[TNF]]-α, myostatin, angiotensin converter enzyme, ApoE, interleukine-12 and -18. Finally, when performing network pharmacology analysis of the target nodes, some compounds were identified as potentially therapeutic (e.g., epigallocatechin gallate and antirheumatic agents); while some other substances appeared to be toxicants that may be involved in the development of this condition.
|mesh-terms=* Aging
* Apoptosis
* Cell Proliferation
* Epigenesis, Genetic
* Frailty
* Genes
* Humans
* Muscle, Smooth
* Pharmacology
* Proteolysis
* Signal Transduction
* Systems Biology

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646318
}}
{{medline-entry
|title=The Age-Related Performance Decline in Marathon Running: The Paradigm of the Berlin Marathon.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31174325
|abstract=The variation of marathon race time by age group has been used recently to model the decline of endurance with aging; however, paradigms of races (i.e., marathon running) examined so far have mostly been from the United States. Therefore, the aim of the present study was to examine the age of peak performance ([[APP]]) in a European race, the "Berlin Marathon". Race times of 387,222 finishers (women, n = 93,022; men, n = 294,200) in this marathon race from 2008 to 2018 were examined. Men were faster by  1.10 km.h  (10.74 ± 1.84 km.h  [i]versus[/i] 9.64 ± 1.46 km.h , [i]p[/i] <0.001, η  = 0.065, medium effect size) and older by  2.1 years (43.1 ± 10.0 years [i]versus[/i] 41.0 ± 9.8 years, [i]p[/i] < 0.001, η  = 0.008, trivial effect size) than women. [[APP]] was 32 years in women and 34 years in men using 1-year age groups, and 30-34 years in women and 35-39 years in men using 5-year age groups. Women's and men's performance at 60-64 and 55-59 age groups, respectively, corresponded to ~90% of the running speed at [[APP]]. Based on these findings, it was concluded that although [[APP]] occurred earlier in women than men, the observed age-related differences indicated that the decline of endurance with aging might differ by sex.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aging
* Athletic Performance
* Berlin
* Female
* Humans
* Male
* Middle Aged
* Nutritional Status
* Physical Endurance
* Running
* Seasons
* Sex Factors
* Young Adult
|keywords=* aerobic capacity
* age of peak performance
* ageing
* exercise
* gender
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603944
}}
{{medline-entry
|title=The db mutation improves memory in younger mice in a model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31034991
|abstract=Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Lepr ) induces mixed or vascular dementia in mature to middle-aged [[APP]]  x PS1  knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aβ content, which we have not observed at older ages. This was unlikely to be related to altered Aβ synthesis, as both β- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1β mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Animals
* Behavior, Animal
* Brain
* Calcium-Binding Proteins
* Diabetes Mellitus, Type 2
* Disease Models, Animal
* Glial Fibrillary Acidic Protein
* Interleukin-1beta
* Memory
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microfilament Proteins
* Receptors, Leptin
* Signal Transduction
* TOR Serine-Threonine Kinases
|keywords=* Alzheimer's disease
* Aβ synthesis
* Cognitive function
* Db mutation
* Glucose regulation
|full-text-url=https://sci-hub.do/10.1016/j.bbadis.2019.04.013
}}
{{medline-entry
|title=Electrophysiological Characterization of Networks and Single Cells in the Hippocampal Region of a Transgenic Rat Model of Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30809590
|abstract=The hippocampus and entorhinal cortex (EC) are areas affected early and severely in Alzheimer's disease (AD), and this is associated with deficits in episodic memory. Amyloid-β (Aβ), the main protein found in amyloid plaques, can affect neuronal physiology and excitability, and several AD mouse models with memory impairments display aberrant network activity, including hyperexcitability and seizures. In this study, we investigated single cell physiology in EC and network activity in EC and dentate gyrus (DG) in the McGill-R-Thy1-[[APP]] transgenic rat model, using whole-cell patch clamp recordings and voltage-sensitive dye imaging (VSDI) in acute slices. In slices from transgenic animals up to 4 months of age, the majority of the principal neurons in Layer II of EC, fan cells and stellate cells, expressed intracellular Aβ (iAβ). Whereas the electrophysiological properties of fan cells were unaltered, stellate cells were more excitable in transgenic than in control rats. Stimulation in the DG resulted in comparable patterns in both groups at three and nine months, but at 12 months, the elicited responses in the transgenic group showed a significant preference for the enclosed blade, without any change in overall excitability. Only transient changes in the local network activity were seen in the medial EC (MEC). Although the observed changes in the McGill rat model are subtle, they are specific, pointing to a differential and selective involvement of specific parts of the hippocampal circuitry in Aβ pathology.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Entorhinal Cortex
* Hippocampus
* Membrane Potentials
* Neural Pathways
* Neurons
* Rats, Transgenic
* Tissue Culture Techniques
|keywords=* entorhinal cortex
* fan cell
* intracellular
* neuronal excitability
* stellate cell
* voltage-sensitive dye imaging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390198
}}
{{medline-entry
|title=Age- and sex-dependent profiles of [[APP]] fragments and key secretases align with changes in despair-like behavior and cognition in young [[APP]]Swe/Ind mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30803762
|abstract=Biological sex exerts distinct influences on brain levels of the β-amyloid (Aβ) peptide in both clinical depression and Alzheimer disease (AD), yet studies in animal models focus primarily on males. We examined behavioral 'despair'/depression (using the tail-suspension test) and memory (using the novel object recognition task) in J20 (h[[APP]] ) mice. Three month-old male (but not female) J20 mice exhibited less despair-like behavior, but more evidence of cognitive deficits. In young J20 mice, only soluble Aβ peptides -primarily Aβ(1-40)- were detected. There was no evidence of an effect on despair-like behavior in the six month-old J20 mice, although cognitive deficits were now evident in both sexes, and coincided with a greater proportion of the neurotoxic Aβ(1-42) species (in soluble as well as insoluble fractions). This age-dependent shift in Aβ peptide profile coincided with reduced expression of glycosylated species of ADAM-10 (α-secretase) and [[BACE1]] (β-secretase), and an increased co-immunoprecipitation of presenilin-1 with nicastrin (components of the γ-secretase complex). Sex-dependent changes in depression-related monoaminergic, e.g. serotonin and dopamine (but not noradrenaline), systems were evident already in young J20 mice. It is critical to acknowledge that sex-dependent [[APP]]-related phenotypes might differentially influence modifiable depression-related monoaminergic signalling at some of the earliest pathological stages of clinical AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Brain
* Cognitive Dysfunction
* Depression
* Disease Models, Animal
* Female
* Humans
* Male
* Mice
* Mice, Transgenic
* Peptide Fragments
|keywords=* Alzheimer
* Amyloid
* Cortex
* Depression
* GABA
* Monoamines
* Sexual dimorphism
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2019.02.083
}}
{{medline-entry
|title=Upregulation of Proteolytic Pathways and Altered Protein Biosynthesis Underlie Retinal Pathology in a Mouse Model of Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30707393
|abstract=Increased amyloid β (Aβ) aggregation is a hallmark feature of Alzheimer's disease (AD) pathology. The [[APP]]/PS1 mouse model of AD exhibits accumulation of Aβ in the retina and demonstrates reduced retinal function and other degenerative changes. The overall molecular effects of AD pathology on the retina remain undetermined. Using a proteomics approach, this study assessed the molecular effects of Aβ accumulation and progression of AD pathology on the retina. Retinal tissues from younger (2.5 months) and older 8-month [[APP]]/PS1 mice were analysed for protein expression changes. A multiplexed proteomics approach using chemical isobaric tandem mass tags was applied followed by functional and protein-protein interaction analyses using Ingenuity pathway (IPA) and STRING computational tools. We identified approximately 2000 proteins each in the younger (upregulated 50; downregulated 36) and older set of [[APP]]/PS1 (upregulated 85; downregulated 79) mice retinas. Amyloid precursor protein ([[APP]]) was consistently upregulated two to threefold in both younger and older retinas (p < 0.0001). Mass spectrometry data further revealed that older [[APP]]/PS1 mice retinas had elevated levels of proteolytic enzymes cathepsin D, presenilin 2 and nicastrin that are associated with [[APP]] processing. Increased levels of proteasomal proteins Psma5, Psmd3 and Psmb2 were also observed in the older AD retinas. In contrast to the younger animals, significant downregulation of protein synthesis and elongation associated proteins such as Eef1a1, Rpl35a, Mrpl2 and Eef1e1 (p < 0.04) was identified in the older mice retinas. This study reports for the first time that not only old but also young [[APP]]/PS1 animals demonstrate increased amyloid protein levels in their retinas. Quantitative proteomics reveals new molecular insights which may represent a cellular response to clear amyloid build-up. Further, downregulation of ribosomal proteins involved in protein biosynthesis was observed which might be considered a toxicity effect.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Disease Models, Animal
* Down-Regulation
* Humans
* Mice, Inbred C57BL
* Mice, Transgenic
* Presenilin-1
* Proteasome Endopeptidase Complex
* Protein Biosynthesis
* Protein Interaction Maps
* Proteolysis
* Proteomics
* Retina
* Up-Regulation
* alpha-Crystallin B Chain
|keywords=* APP/PS1
* Alzheimer's disease
* Amyloid beta
* Quantitative proteomics
* Retina
* Tandem mass tag
|full-text-url=https://sci-hub.do/10.1007/s12035-019-1479-4
}}
{{medline-entry
|title=Soluble Amyloid Precursor Protein α: Friend or Foe?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30637698
|abstract=The "amyloidogenic" proteolytic processing of the cell surface amyloid precursor protein ([[APP]]) produces amyloid-β, which causes a range of detrimental effects in the neuron, such as synaptic loss, and plays a key role in Alzheimer's disease. In contrast, "non-amyloidogenic" proteolytic processing, which involves the cleavage of [[APP]] by α-secretase, produces soluble amyloid precursor protein α (s[[APP]]α) and is the most predominant proteolytic processing of [[APP]] in the healthy brain. Current research suggests that s[[APP]]α plays a role in synaptic growth and plasticity, but whether this role is protective or detrimental is age-dependent. This review looks at the effects of increasing s[[APP]]α during three time-points in life (in development, young adult, ageing/neurodegeneration) when synaptic plasticity plays an important role.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Brain
* Humans
* Neurodegenerative Diseases
* Neuronal Plasticity
|keywords=* A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10)
* Ageing
* Amyloid precursor protein (APP)
* Dendritic spines
* Development
* Neurodegeneration
* Neuroprotection
* Soluble amyloid precursor protein α (sAPPα)
* Synaptic plasticity
|full-text-url=https://sci-hub.do/10.1007/978-981-13-3065-0_13
}}
{{medline-entry
|title=Amyloid Precursor Protein Mediates Neuronal Protection from Rotenone Toxicity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30612335
|abstract=Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein ([[APP]]) and its non-amyloidogenic processing products, in particular soluble [[APP]] α (s[[APP]]α), have been shown to provide neuroprotection in models of neuronal injury; however, [[APP]]-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of [[APP]] and s[[APP]]α in vitro, in neuronal cell lines over-expressing [[APP]], and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that [[APP]] over-expression is protective against rotenone toxicity in neurons via s[[APP]]α through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. [[APP]]  mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of s[[APP]]α reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of [[APP]] with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of [[APP]] in complex I-related neurodegeneration.
|mesh-terms=* Adenosine Triphosphate
* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Amyloid beta-Protein Precursor
* Animals
* Cell Line, Tumor
* Child
* Child, Preschool
* Enzyme Activation
* Female
* Humans
* Male
* Mice
* Middle Aged
* Mitochondria
* Neurons
* Neuroprotection
* Neuroprotective Agents
* Phosphatidylinositol 3-Kinases
* Proto-Oncogene Proteins c-akt
* Reactive Oxygen Species
* Rotenone
* Toxicity Tests
* Young Adult
|keywords=* Amyloid precursor protein
* Complex I
* Mitochondria
* Neuroprotection
* Retina
* Rotenone
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614131
}}
{{medline-entry
|title=Selective reduction of [[APP]]-[[BACE1]] activity improves memory via NMDA-NR2B receptor-mediated mechanisms in aged PD[[APP]] mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30572184
|abstract=β-Amyloid (Aβ) accumulation is an early event of Alzheimer's disease (AD) pathogenesis. Inhibition of Aβ production by β-secretase (BACE) has been proposed as a potential therapeutic strategy for AD. However, BACE inhibitors lack specificity and have had limited clinical benefit. To better study the consequences of reducing BACE metabolism, specifically of [[APP]], we used an antibody, 2B3, that binds to [[APP]] at the BACE cleavage site, inhibiting Aβ production. 2B3 was administered either directly into the lateral ventricles or by intraperitoneal injection to (platelet-derived growth factor promoter h[[APP]]717V (PD[[APP]]) mice and WT mice. 2B3 reduced soluble Aβ40 and βCTF (β-amyloid derived C-terminal fragment) and improved memory for object-in-place associations and working memory in a foraging task in PD[[APP]] mice. 2B3 also normalized the phosphorylation of the N-methyl-D-aspartate receptor NR2B subunit and subsequent extracellular signal-regulated kinase signaling. The importance of this NR2B pathway for OiP memory was confirmed by administering the NR2B antagonist, Ro25-6981, to 18-month-old WT. In contrast, 2B3 impaired associative recognition memory in young WT mice. These data provide novel insights into the mechanism by which selective modulation of [[APP]] metabolism by BACE influences synaptic and cognitive processes in both normal mice and aged [[APP]] transgenic mice.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Male
* Memory
* Mice, Transgenic
* N-Methylaspartate
* Receptors, N-Methyl-D-Aspartate
|keywords=* Amyloid
* Amyloid precursor protein
* BACE1
* Hippocampus
* Memory
* NMDA
* βCTF antibody
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357873
}}
{{medline-entry
|title=Effect of Resistance Training and Fish Protein Intake on Motor Unit Firing Pattern and Motor Function of Elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30564141
|abstract=We investigated the effect of resistance training and fish protein intake on the motor unit firing pattern and motor function in elderly. Fifty healthy elderly males and females (69.2 ± 4.7 years) underwent 6 weeks of intervention. We applied the leg-press exercise as resistance training and fish protein including Alaska pollack protein ([[APP]]) as nutritional supplementation. Subjects were divided into four groups: fish protein intake without resistance training ([[APP]]-CN, [i]n[/i] = 13), placebo intake without resistance training (PLA-CN, [i]n[/i] = 12), fish protein intake with resistance training ([[APP]]-RT, [i]n[/i] = 12), and placebo intake with resistance training (PLA-RT, [i]n[/i] = 13). Motor unit firing rates were calculated from multi-channel surface electromyography by the Convolution Kernel. For the chair-stand test, while significant increases were observed at 6 weeks compared with 0 week in all groups ([i]p[/i] < 0.05), significant increases from 0 to 3 weeks and 6 weeks were observed in [[APP]]-RT (18.2 ± 1.9 at 0 week to 19.8 ± 2.2 at 3 weeks and 21.2 ± 1.9 at 6 weeks) ([i]p[/i] < 0.05). Increase and/or decrease in the motor unit firing rate were mainly noted within motor units with a low-recruitment threshold in [[APP]]-RT and PLA-RT at 3 and 6 weeks (12.3 pps at 0 week to 13.6 pps at 3 weeks and 12.1 pps at 6 weeks for [[APP]]-RT and 12.9 pps at 0 week to 13.9 pps at 3 weeks and 14.1 pps at 6 weeks for PLA-RT at 50% of MVC) ([i]p[/i] < 0.05), but not in [[APP]]-CN or PLA-CN ([i]p[/i] > 0.05). Time courses of changes in the results of the chair-stand test and motor unit firing rate were different between [[APP]]-RT and PLA-RT. These findings suggest that, in the elderly, the effect of resistance training on the motor unit firing rate is observed in motor units with a low-recruitment threshold, and additional fish protein intake modifies these adaptations in motor unit firing patterns and the motor function following resistance training.

|keywords=* aging
* countermeasures to aging
* motor unit decomposition
* multichannel surface electromyography
* nutritional supplementation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288440
}}
{{medline-entry
|title=The amyloid precursor protein ([[APP]]) processing as a biological link between Alzheimer's disease and cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30500566
|abstract=Aging is a risk factor for several illnesses, such as Alzheimer's Disease and various cancers. However, an inverse correlation between malignancies and Alzheimer's Disease has been suggested. This review addressed the potential role of non-amyloidogenic and amyloidogenic pathways of amyloid precursor protein processing as a relevant biochemical mechanism to clarify this association. Amyloidogenic and non-amyloidogenic pathways have been related to Alzheimer's Disease and certain malignancies, respectively. Several known molecules involved in [[APP]] processing, including its regulation and final products, were summarized. Among them some candidate mechanisms emerged, such as extracellular-regulated kinase (Erk) and protein kinase C (PKC). Therefore, the imbalance of [[APP]] processing may be involved with the negative correlation between cancer and Alzheimer Disease.
|mesh-terms=* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Humans
* Neoplasms
|keywords=* Aging
* Alzheimer disease
* Amyloid precursor protein
* Amyloidogenic pathway
* Cancer
* Non- amyloidogenic pathway
|full-text-url=https://sci-hub.do/10.1016/j.arr.2018.11.007
}}
{{medline-entry
|title=Microglial response to increasing amyloid load saturates with aging: a longitudinal dual tracer in vivo μPET-study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30400912
|abstract=Causal associations between microglia activation and β-amyloid (Aβ) accumulation during the progression of Alzheimer's disease (AD) remain a matter of controversy. Therefore, we used longitudinal dual tracer in vivo small animal positron emission tomography (μPET) imaging to resolve the progression of the association between Aβ deposition and microglial responses during aging of an Aβ mouse model. [[APP]]-SL70 mice (N = 17; baseline age 3.2-8.5 months) and age-matched C57Bl/6 controls (wildtype (wt)) were investigated longitudinally for 6 months using Aβ (18F-florbetaben) and 18 kDa translocator protein ([[[[TSPO]]]]) μPET (18F-GE180). Changes in cortical binding were transformed to Z-scores relative to wt mice, and microglial activation relative to amyloidosis was defined as the Z-score difference ([[[[TSPO]]]]-Aβ). Using 3D immunohistochemistry for activated microglia (Iba-1) and histology for fibrillary Aβ (methoxy-X04), we measure microglial brain fraction relative to plaque size and the distance from plaque margins. Aβ-PET binding increased exponentially as a function of age in [[APP]]-SL70 mice, whereas [[[[TSPO]]]] binding had an inverse U-shape growth function. Longitudinal Z-score differences declined with aging, suggesting that microglial response declined relative to increasing amyloidosis in aging [[APP]]-SL70 mice. Microglial brain volume fraction was inversely related to adjacent plaque size, while the proximity to Aβ plaques increased with age. Microglial activity decreases relative to ongoing amyloidosis with aging in [[APP]]-SL70 mice. The plaque-associated microglial brain fraction saturated and correlated negatively with increasing plaque size with aging.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Amyloidosis
* Animals
* Calcium-Binding Proteins
* Carbazoles
* Disease Models, Animal
* Fluorodeoxyglucose F18
* Longitudinal Studies
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microfilament Proteins
* Microglia
* Positron-Emission Tomography
* Radiochemistry
* Receptors, GABA
|keywords=* Aging
* Alzheimer’s disease
* Amyloid μPET
* Microglia
* Neuroinflammation
* TSPO μPET
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220478
}}
{{medline-entry
|title=Analysis of Motor Function in Amyloid Precursor-Like Protein 2 Knockout Mice: The Effects of Ageing and Sex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30362021
|abstract=The amyloid precursor protein ([[APP]]) is a member of a conserved gene family that includes the amyloid precursor-like proteins 1 (APLP1) and 2 ([[APLP2]]). [[APP]] and [[APLP2]] share a high degree of similarity, and have overlapping patterns of spatial and temporal expression in the central and peripheral tissues, in particular at the neuromuscular junction. [[APP]]-family knockout (KO) studies have helped elucidate aspects of function and functional redundancy amongst the [[APP]]-family members. In the present study, we investigated motor performance of [[APLP2]]-KO mice and the effect sex differences and age-related changes have on motor performance. [[APLP2]]-KO and WT (on C57Bl6 background) littermates control mice from 8 (young adulthood) to 48 weeks (middle age) were investigated. Analysis of motor neuron and muscle morphology showed [[APLP2]]-KO females but not males, had less age-related motor function impairments. We observed age and sex differences in both motor neuron number and muscle fiber size distribution for [[APLP2]]-KO mice compared to WT (C57Bl6). These alterations in the motor neuron number and muscle fiber distribution pattern may explain why female [[APLP2]]-KO mice have far better motor function behaviour during ageing.
|mesh-terms=* Age Factors
* Aging
* Amyloid beta-Protein Precursor
* Animals
* Female
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Motor Activity
* Motor Neurons
* Muscle, Skeletal
* Sex Factors
* Spinal Cord
|keywords=* Ageing
* Amyloid precursor protein
* Amyloid precursor-like protein
* Knockout
* Motor neurons
* Sex differences
|full-text-url=https://sci-hub.do/10.1007/s11064-018-2669-6
}}
{{medline-entry
|title=Increased Insoluble Amyloid-β Induces Negligible Cognitive Deficits in Old AppNL/NL Knock-In Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30320577
|abstract=Commonly used Alzheimer's disease mouse models are based on the ectopic overexpression of the human amyloid precursor protein ([[APP]]) gene, together with a mutant presenilin gene. Surprisingly, humanized [[APP]] knock-in mouse models carrying a single [[APP]] Swedish mutation (AppNL), failed to develop amyloid plaque aggregation or cognitive deficits. Here we characterized the effect of this mutation in more advanced ages. We show that 24-month-old AppNL/NL mice, despite presenting an age dependent increase in insoluble amyloid-β oligomers in the prefrontal cortex, they do not develop amyloid plaque deposition, reactive gliosis, or cognitive deficits.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Cognitive Dysfunction
* Conditioning, Psychological
* Cues
* Disease Models, Animal
* Exploratory Behavior
* Fear
* Gene Expression Regulation
* Male
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Mutation
* Prefrontal Cortex
* Social Behavior
|keywords=* Aging
* Alzheimer’s disease
* amyloid plaques
* behavior
* cognition
* knock-in
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218137
}}
{{medline-entry
|title=Long-term dietary supplementation with the green tea cultivar Sunrouge prevents age-related cognitive decline in the senescence-accelerated mouse Prone8.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30295144
|abstract=A majority of the potential health benefits of green tea, including the potential to prevent cognitive decline, have been attributed to epigallocatechin gallate (EGCG). Sunrouge is a green tea cultivar that contains EGCG and several other bioactive components such as quercetin, myricetin, cyanidin and delphinidin. We compared the effects of Sunrouge and Yabukita, the most popular Japanese green tea cultivar, on cognitive function in the senescence-accelerated mouse Prone8. These mice were fed an experimental diet containing Sunrouge extract (SRE) or Yabukita extract (YBE). SRE feeding significantly prevented cognitive decline, whereas YBE feeding had little effect. Moreover, SRE feeding prevented elevation of the amyloid-β42 level while improving the gene expression of neprilysin and decreasing beta-site [[APP]]-cleaving enzyme 1 in the brain. These preventive effects of SRE against cognitive decline were attributed to the characteristic composition of Sunrouge and strongly suggest that consumption of this cultivar could protect against age-related cognitive decline.
|mesh-terms=* Acetylcholinesterase
* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Cognition Disorders
* Dietary Supplements
* Enzymes
* Male
* Mice
* Mice, Mutant Strains
* Neprilysin
* Peptide Fragments
* Tea
|keywords=* Green tea
* Sunrouge
* cognitive decline
* delphinidin
* myricetin
|full-text-url=https://sci-hub.do/10.1080/09168451.2018.1530093
}}
{{medline-entry
|title=Axonal organization defects in the hippocampus of adult conditional [[BACE1]] knockout mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30232227
|abstract=β-Site [[APP]] (amyloid precursor protein) cleaving enzyme 1 ([[BACE1]]) is the β-secretase enzyme that initiates production of the toxic amyloid-β peptide that accumulates in the brains of patients with Alzheimer's disease (AD). Hence, [[BACE1]] is a prime therapeutic target, and several [[BACE1]] inhibitor drugs are currently being tested in clinical trials for AD. However, the safety of [[BACE1]] inhibition is unclear. Germline [[BACE1]] knockout mice have multiple neurological phenotypes, although these could arise from [[BACE1]] deficiency during development. To address this question, we report that tamoxifen-inducible conditional [[BACE1]] knockout mice in which the [i]Bace1[/i] gene was ablated in the adult largely lacked the phenotypes observed in germline [[BACE1]] knockout mice. However, one [[BACE1]]-null phenotype was induced after [i]Bace1[/i] gene deletion in the adult mouse brain. This phenotype showed reduced length and disorganization of the hippocampal mossy fiber infrapyramidal bundle, the axonal pathway of dentate gyrus granule cells that is maintained by neurogenesis in the mouse brain. This defect in axonal organization correlated with reduced [[BACE1]]-mediated cleavage of the neural cell adhesion protein close homolog of L1 (CHL1), which has previously been associated with axon guidance. Although our results indicate that [[BACE1]] inhibition in the adult mouse brain may avoid phenotypes associated with [[BACE1]] deficiency during embryonic and postnatal development, they also suggest that [[BACE1]] inhibitor drugs developed for treating AD may disrupt the organization of an axonal pathway in the hippocampus, an important structure for learning and memory.
|mesh-terms=* Aging
* Amyloid Precursor Protein Secretases
* Animals
* Animals, Newborn
* Apoptosis
* Aspartic Acid Endopeptidases
* Axons
* Cognition
* Epilepsy
* Gene Deletion
* Hippocampus
* Long-Term Potentiation
* Memory Disorders
* Mice, Inbred C57BL
* Mice, Knockout
* Myelin Sheath
* Neurogenesis
* Phenotype
* Substrate Specificity

|full-text-url=https://sci-hub.do/10.1126/scitranslmed.aao5620
}}
{{medline-entry
|title=The age of peak performance in women and men duathletes - The paradigm of short and long versions in "Powerman Zofingen".
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30140162
|abstract=The age of peak performance ([[APP]]) has been studied extensively in various endurance and ultra-endurance sports; however, less information exists in regard to duathlon (ie, Run1, Bike, and Run2). The aim of the present study was to assess the [[APP]] of duathletes competing either in a short (ie, 10 km Run1, 50 km Bike, and 5 km Run2) or a long distance (ie, 10 km Run1, 150 km Bike, and 30 km Run2) race. We analyzed 6,671 participants (women, n=1,037, age 36.6±9.1 years; men, n=5,634, 40.0±10.0 years) in "Powerman Zofingen" from 2003 to 2017. Considering the finishers in 5-year age groups, in the short distance, a small main effect of sex on race time was observed ([i]p[/i]<0.001, η  =0.052) with men (171.7±20.9 min) being faster than women (186.0±21.5 min) by -7.7%. A small main effect of age group on race was shown ([i]p[/i]<0.001, η  =0.049) with 20-24 years being the fastest and 70-74 years the slowest. No sex × age group interaction was found ([i]p[/i]=0.314, η  =0.003). In the long distance, a small main effect of sex on race time was observed ([i]p[/i]<0.001, η  =0.021) with men (502.8±56.8 min) being faster than women (544.3±62.8 min) by -7.6%. A large main effect of age group on race time was shown ([i]p[/i]<0.001, η  =0.138) with age group 25-29 years the fastest and age group 70-74 years the slowest. A small sex × age group interaction on race time was found ([i]p[/i]<0.001, η  =0.013) with sex difference ranging from -22.4% (15-19 age group) to -6.6% (30-34 age group). Based on these findings, it was concluded an older [[APP]] in the long than in the short distance was seen in "Powerman Zofingen." This indicates that [[APP]] in duathlon follows a similar trend as in endurance and ultra-endurance running and triathlon, ie, the longer the distance, the older the [[APP]].

|keywords=* aging
* cycling
* master athletes
* running
* ultra-endurance
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054758
}}
{{medline-entry
|title=Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30112699
|abstract=Proteolytic cleavage of the amyloid precursor protein ([[APP]]) into the Aβ peptide has been an extensively researched mechanism for Alzheimer's disease, but the normal function of the protein is less understood. [[APP]] functions to regulate neuronal iron content by stabilizing the surface presentation of ferroportin-the only iron exporter channel of cells. The present study aims to quantify the contribution of [[APP]] to brain and peripheral iron by examining the lifetime impact on brain and liver iron levels in [[APP]] knockout mice. Consistent with previous reports, we found that wild-type mice exhibited an age-dependent increase in iron and ferritin in the brain, while no age-dependent changes were observed in the liver. [[APP]] ablation resulted in an exaggeration of age-dependent iron accumulation in the brain and liver in mice that was assessed at 8, 12, 18, and 22 months of age. Brain ferroportin levels were decreased in [[APP]] knockout mice, consistent with a mechanistic role for [[APP]] in stabilizing this iron export protein in the brain. Iron elevation in the brain and liver of [[APP]] knockout mice correlated with decreased transferrin receptor 1 and increased ferritin protein levels. However, no age-dependent increase in brain ferritin iron saturation was observed in [[APP]]-KO mice despite similar protein expression levels potentially explaining the vulnerability of [[APP]]-KO mice to parkinsonism and traumatic brain sequelae. Our results support a crucial role of [[APP]] in regulating brain and peripheral iron, and show that [[APP]] may act to oppose brain iron elevation during aging.
|mesh-terms=* Age Factors
* Aging
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Ferritins
* Iron
* Liver
* Mice
* Mice, Knockout
|keywords=* Amyloid precursor protein
* Brain
* Ferritin
* Iron
* Neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277293
}}
{{medline-entry
|title=Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30071357
|abstract=Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) [[CXCL10]] (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), [[CX3CL1]] (C-X3-C motif chemokine ligand 1), (2) [[GDF15]] (growth differentiation factor 15), [[FNDC5]] (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) [[PLAU]] (plasminogen activator, urokinase), [[AGT]] (angiotensinogen), (5) [[BDNF]] (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), [[FGF23]] (fibroblast growth factor 23), [[FGF21]], leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), [[AHCY]] (adenosylhomocysteinase) and [[KRT18]] (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) [[APP]] (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) [[S100B]] (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), [[TGM2]] (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), [[HMGB1]] (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.
|mesh-terms=* Aged
* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Apoptosis
* Biomarkers
* Fibronectins
* Frailty
* Genetic Association Studies
* Growth Differentiation Factor 15
* Humans
* Insulin-Like Growth Factor I
* Interleukin-1 Receptor-Like 1 Protein
* Membrane Glycoproteins
* MicroRNAs
* Signal Transduction
|keywords=* Age-related diseases
* Biomarker panel
* Frailty
* Hallmark of aging pathways
|full-text-url=https://sci-hub.do/10.1016/j.arr.2018.07.004
}}
{{medline-entry
|title=DNA methylation analysis on purified neurons and glia dissects age and Alzheimer's disease-specific changes in the human cortex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30045751
|abstract=Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as [[CLU]], [[SYNJ2]] and [[NCOR2]] or in glia [[RAI1]],CXXC5 and [[INPP5A]]. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as [[MCF2L]], [[ANK1]], [[MAP2]], [[LRRC8B]], [[STK32C]] and [[S100B]]. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., [[HOXA3]] or glia ([[ANK1]]). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes [[APP]] and [[ADAM17]]. Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.
|mesh-terms=* ADAM17 Protein
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Autopsy
* Cell Separation
* DNA Methylation
* Epigenesis, Genetic
* Epigenomics
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Neuroglia
* Neurons
* Organ Specificity
* Transcriptome
|keywords=* Aging
* Alzheimer’s disease
* Brain
* Cell sorting
* DNA methylation
* EWAS
* Epigenetics
* Glia
* Neurodegeneration
* Neuron
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058387
}}
{{medline-entry
|title=Alterations of functional circuitry in aging brain and the impact of mutated [[APP]] expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30055413
|abstract=Alzheimer's disease (AD) is a disease of aging that results in cognitive impairment, dementia, and death. Pathognomonic features of AD are amyloid plaques composed of proteolytic fragments of the amyloid precursor protein ([[APP]]) and neurofibrillary tangles composed of hyperphosphorylated tau protein. One type of familial AD occurs when mutant forms of [[APP]] are inherited. Both [[APP]] and tau are components of the microtubule-based axonal transport system, which prompts the hypothesis that axonal transport is disrupted in AD, and that such disruption impacts cognitive function. Transgenic mice expressing mutated forms of [[APP]] provide preclinical experimental systems to study AD. Here, we perform manganese-enhanced magnetic resonance imaging to study transport from hippocampus to forebrain in four cohorts of living mice: young and old wild-type and transgenic mice expressing a mutant [[APP]] with both Swedish and Indiana mutations ([[APP]]SwInd). We find that transport is decreased in normal aging and further altered in aged [[APP]]SwInd plaque-bearing mice. These findings support the hypothesis that transport deficits are a component of AD pathology and thus may contribute to cognitive deficits.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Axonal Transport
* Hippocampus
* Humans
* Mice, Inbred C57BL
* Mice, Transgenic
* Neural Pathways
* Prosencephalon
|keywords=* Aging
* Amyloid precursor protein (APP)
* CA3 of the hippocampus
* Cholinergic neurons
* Dentate gyrus
* Fast axonal transport
* Manganese-enhanced magnetic resonance imaging (MEMRI)
* Septal nuclei
* Transgenic mice for Alzheimer's disease investigation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159914
}}
{{medline-entry
|title=Menadione sodium bisulfite inhibits the toxic aggregation of amyloid-β(1-42).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30036601
|abstract=Protein misfolding and aggregation are associated with amyloidosis. The toxic aggregation of amyloid-β 1-42 (Aβ42) may disrupt cell membranes and lead to cell death and is thus regarded as a contributing factor in Alzheimer's disease (AD). 1,4-naphthoquinone (NQ) has been shown to exhibit strong anti-aggregation effects on amyloidogenic proteins such as insulin and α-synuclein; however, its high toxicity and poor solubility limit its clinical application. Menadione sodium bisulfite (MSB, also known as vitamin K3), is used clinically in China to treat hemorrhagic diseases caused by vitamin K deficiency and globally as a vitamin K supplement. We hypothesized that MSB could inhibit amyloid formation since its backbone structure is similar to NQ. To test our hypothesis, we first investigated the effects of MSB on Aβ42 amyloid formation in vitro. We found that MSB inhibited Aβ42 amyloid formation in a dose dependent manner, delayed the secondary structural conversion of Aβ42 from random coil to ordered β-sheet, and attenuated the ability of Aβ42 aggregates to disrupt membranes; moreover, the quinone backbone rather than lipophilicity is esstial for the inhibitory effects of MSB. Next, in cells expressing a pathogenic [[APP]] mutation (Osaka mutation) that results in the formation of intraneuronal Aβ oligomers, MSB inhibited the intracellular aggregation of Aβ. Moreover, MSB treatment significantly extended the life span of Caenorhabditis elegans CL2120, a strain that expresses human Aβ42. Together, these results suggest that MSB and its derivatives may be further explored as potential therapeutic agents for the prevention or treatment of AD.
|mesh-terms=* Amyloid beta-Peptides
* Animals
* Animals, Genetically Modified
* Caenorhabditis elegans
* Humans
* Longevity
* Peptide Fragments
* Protein Aggregation, Pathological
* Vitamin K 3
* Vitamins
|keywords=* 1,4-naphthoquinone
* Aggregation
* Amyloid
* Aβ42
* Caenorhabditis elegans
* Menadione sodium bisulfite
|full-text-url=https://sci-hub.do/10.1016/j.bbagen.2018.07.019
}}
{{medline-entry
|title=Sirtuin 1 and Alzheimer's disease: An up-to-date review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30007474
|abstract=Sirtuins are NAD -dependent enzymes that regulate a large number of cellular pathways and are related to aging and age-associated diseases. In recent years, the role of sirtuins in Alzheimer's disease (AD) has become increasingly apparent. Growing evidence demonstrates that sirtuin 1 ([[SIRT1]]) regulates many processes that go amiss in AD, such as: [[APP]] processing, neuroinflammation, neurodegeneration, and mitochondrial dysfunction. Here we review how [[SIRT1]] affects AD and cognition, the main mechanisms in which [[SIRT1]] is related to AD pathology, and its importance for the prevention and possible diagnosis of AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Cognition
* Humans
* Sirtuin 1
|keywords=* Alzheimer's disease
* Cognition
* Neurodegeneration
* SIRT1
* Sirtuins
|full-text-url=https://sci-hub.do/10.1016/j.npep.2018.07.001
}}
{{medline-entry
|title=Biliverdin reductase-A impairment links brain insulin resistance with increased Aβ production in an animal model of aging: Implications for Alzheimer disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29981845
|abstract=Brain insulin resistance is associated with an increased Aβ production in AD although the molecular mechanisms underlying this link are still largely unknown. Biliverdin reductase-A (BVR-A) is a unique Ser/Thr/Tyr kinase regulating insulin signalling. Studies from our group, demonstrated that BVR-A impairment is among the earliest events favoring brain insulin resistance development. Furthermore, reported a negative association between BVR-A protein levels/activation and [[BACE1]] protein levels in the parietal cortex of aged beagles (an animal model of AD), thus suggesting a possible interaction. Therefore, we aimed to demonstrate that BVR-A impairment is a molecular bridge linking brain insulin resistance with increased Aβ production. Age-associated changes of BVR-A, [[BACE1]], insulin signalling cascade and [[APP]] processing were evaluated in the parietal cortex of beagles and experiments to confirm the hypothesized mechanism(s) have been performed in vitro in HEK293[[APP]]swe cells. Our results show that BVR-A impairment occurs early with age and is associated with brain insulin resistance. Furthermore, we demonstrate that BVR-A impairment favors CK1-mediated Ser phosphorylation of [[BACE1]] (known to mediate [[BACE1]] recycling to plasma membrane) along with increased Aβ production in the parietal cortex, with age. Overall, our results suggest that the impairment of BVR-A is an early molecular event contributing to both (I) the onset of brain insulin resistance and (II) the increased Aβ production observed in AD. We, therefore, suggest that by targeting BVR-A activity it could be possible to delay the onset of brain insulin resistance along with an improved regulation of the [[APP]] processing.
|mesh-terms=* Aged
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Brain
* Cyclin-Dependent Kinase Inhibitor Proteins
* Disease Models, Animal
* Dogs
* HEK293 Cells
* Humans
* Insulin Resistance
* Male
* Oxidoreductases Acting on CH-CH Group Donors
* Phosphorylation
|keywords=* Alzheimer disease
* BACE1
* Bilivedin reductase-A
* Canine
* Dog
* Insulin resistance
|full-text-url=https://sci-hub.do/10.1016/j.bbadis.2018.07.005
}}
{{medline-entry
|title=Human Cord Blood Serum-Derived [[APP]] α-Secretase Cleavage Activity is Mediated by C1 Complement.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29871524
|abstract=Alzheimer's Disease (AD) is the leading cause of dementia in the elderly. In healthy individuals, amyloid precursor protein ([[APP]]) is cleaved by α-secretase, generating soluble α-amyloid precursor protein (s[[APP]]α), which contributes neuroprotective functions in the neuronal environment. In contrast, in the neurodegenerative environment of AD patients, amyloid-β-peptide (Aβ) of either 40 or 42 residues are generated by increased activity of β- and γ-secretase. These proteins amalgamate in specific regions of the brain, which disrupts neuronal functions and leads to cognitive impairment. Human umbilical cord blood cells (HUCBC) have proven useful as potential immunomodulatory therapies in various models of neurodegenerative diseases, including AD. Our most recent work studied the impact of umbilical cord blood serum ([[CBS]]) on modulation of s[[APP]]α production. Heat-sensitive [[CBS]] significantly promoted s[[APP]]α production, indicating that heat-sensitive factor(s) play(s) a role in this process. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis was used to determine the molecular source of α-secretase in purified [[CBS]] and aged blood serum (AgBS) fraction. Of the proteins identified, the subunits of C1 complex (C1q, C1r, and C1s) and alpha-2-macroglobulin showed significantly greater levels in purified α-[[CBS]] fraction (α-[[CBS]]F) compared with the AgBS fraction (AgBSF). Specifically, C1 markedly increased s[[APP]]α and alpha-carboxyl-terminal fragment (α-CTF) production in a dose-dependent fashion, whereas C1q alone only minimally increased and [[C3]] did not increase s[[APP]]α production in the absence of sera. Furthermore, C1q markedly increased s[[APP]]α and α-CTF, while decreasing Aβ, in CHO/[[APP]]wt cells cultured in the presence of whole sera. These results confirm our initial assumption that [[APP]] α-secretase activity in human blood serum is mediated by complement C1, opening a potential therapeutic modality for the future of AD.
|mesh-terms=* Aged
* Aging
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Animals
* CHO Cells
* Complement C1
* Complement C3b
* Cricetinae
* Cricetulus
* Fetal Blood
* Hot Temperature
* Humans
* Mice
* Proteomics
|keywords=* Alzheimer’s Disease
* Aβ
* amyloid precursor protein
* complement C1 complex
* complement system
* cord blood serum
* human umbilical cord blood cell
* soluble α-amyloid precursor protein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020233
}}
{{medline-entry
|title=Interaction between a [[MAPT]] variant causing frontotemporal dementia and mutant [[APP]] affects axonal transport.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29729423
|abstract=In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old [[MAPT]]  knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger [[MAPT]]  mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young [[MAPT]]  knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, [[MAPT]]  impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Axonal Transport
* Brain
* Disease Models, Animal
* Frontotemporal Dementia
* Genetic Association Studies
* Genetic Variation
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria
* Mutation
* Plaque, Amyloid
* tau Proteins
|keywords=* Alzheimer's disease
* Axonal transport
* Aβ
* FTDP-17T
* Mitochondria
* P301L mutation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998378
}}
{{medline-entry
|title=Blood-Brain Barrier Disruption and Perivascular Beta-Amyloid Accumulation in the Brain of Aged Rats with Spontaneous Hypertension: Evaluation with Dynamic Contrast-Enhanced Magnetic Resonance Imaging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29713228
|abstract=Whether blood-brain barrier (BBB) disruption induced by chronic spontaneous hypertension is associated with beta-amyloid (Aβ) accumulation in the brain remains poorly understood. The purpose of this study was to investigate the relationship between BBB disruption and Aβ influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. Five aged spontaneously hypertensive rats (SHRs) and five age-matched normotensive Wistar-Kyoto (WKY) rats were studied. The volume transfer constant (K ) obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to evaluate BBB permeability in the hippocampus and cortex [i]in vivo[/i]. The BBB tight junctions, immunoglobulin G (IgG), Aβ, and amyloid precursor protein ([[APP]]) in the hippocampus and cortex were examined with immunohistochemistry. As compared with WKY rats, the K  values in the hippocampus and cortex of the SHRs increased remarkably (0.316 ± 0.027 min  vs. 0.084 ± 0.017 min , [i]p[/i] < 0.001 for hippocampus; 0.302 ± 0.072 min  vs. 0.052 ± 0.047 min , [i]p[/i] < 0.001 for cortex). Dramatic occludin and zonula occludens-1 losses were detected in the hippocampus and cortex of SHRs, and obvious IgG exudation was found there. Dramatic Aβ accumulation was found and limited to the area surrounding the BBB, without extension to other parenchyma regions in the hippocampus and cortex of aged SHRs. Alternatively, differences in [[APP]] expression in the hippocampus and cortex were not significant. Blood-brain barrier disruption is associated with Aβ influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. DCE-MRI can be used as an effective method to investigated BBB damage.
|mesh-terms=* Aging
* Amyloid
* Amyloid beta-Protein Precursor
* Animals
* Blood-Brain Barrier
* Brain
* Cerebellar Cortex
* Contrast Media
* Hippocampus
* Hypertension
* Immunoglobulin G
* Magnetic Resonance Imaging
* Male
* Rats
* Rats, Inbred SHR
* Rats, Wistar
|keywords=* Alzheimer's disease
* Tight junction protein
* Transfer constant
* Transmembrane glycoprotein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904477
}}
{{medline-entry
|title=Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29478851
|abstract=The β-amyloid precursor protein ([[APP]]) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. [[APP]] is cleaved by various secretases whereby sequential processing by the β- and γ-secretases produces the β-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal s[[APP]]β fragments and the [[APP]] intracellular domain (AICD). Alternative cleavage by α-secretase results in slightly longer secreted s[[APP]]α fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, s[[APP]]α fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of s[[APP]]α in [[APP]]-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila [[APP]]-like ([[APP]]L) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted [[APP]]L fragment [3]. We now show that [[APP]]L is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of [[APP]]L in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of [[APP]]L can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length [[APP]]L and that [[APP]]L negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of [[APP]]L or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct [[APP]]L products.
|mesh-terms=* Aging
* Amyloid Precursor Protein Secretases
* Animals
* Drosophila Proteins
* Drosophila melanogaster
* Membrane Proteins
* Memory, Short-Term
* Nerve Tissue Proteins
* Visual Perception
|keywords=* Amyloid Precursor Protein
* Drosophila
* Fasciclin 2
* age-related memory impairment
* central complex
* visual orientation
* working memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840017
}}
{{medline-entry
|title=β-amyloid expression in age-related cataract lens epithelia and the effect of β-amyloid on oxidative damage in human lens epithelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29386875
|abstract=To evaluate the changes in β-amyloid (Aβ) expression in age-related cataract ([[ARC]]) lens epithelia and the effect of Aβ on oxidative damage in human lens epithelial cells (HLECs). Specimens of lens epithelia and aqueous humor were obtained from 255 cataract surgery patients and 48 healthy donor eyes. The [[ARC]] samples were divided into four groups according to the Lens Opacities Classification System III, with increasing severity from Group I to Group IV. The HLECs were cultured under healthy or oxidative conditions with or without Aβ pretreatment. Western blot, immunofluorescence, real-time PCR, and enzyme-linked immunosorbent assay were performed to detect Aβ and β-amyloid precursor protein ([[APP]]) expression. β-secretase activity was analyzed in lens epithelia and HLECs. The effect of Aβ on the viability of HLECs under oxidative conditions was investigated using a cell viability assay. Compared with the healthy group, the Aβ 1-42 expression levels in lens epithelia and Aβ 1-40 expression levels in aqueous humor decreased in Groups I, II, and III (p<0.05) but were unchanged in Group IV. In contrast, [[APP]] expression levels increased in Groups I, II, and III (p<0.05) compared with those in the healthy group but were unchanged in Group IV. H O -treated HLECs exhibited decreased amounts of Aβ 1-42 and increased amounts of [[APP]]. β-secretase activity decreased in the lens epithelia of all four subgroups of [[ARC]]s compared with that in the lens epithelia of healthy subjects and decreased in H O -treated HLECs. Furthermore, treatment with nanomolar concentrations (0.2 nM to 10 nM) of Aβ could protect cell viability from oxidative damage. Aβ and [[APP]] expression levels exhibited differential changes during the development of [[ARC]], indicating active feedback of this protein processing. Decreased expression of physiologically generated Aβ in the early and mid-stages of [[ARC]] development might be one of the potential mechanisms accelerating oxidative stress in HLECs during cataractogenesis.
|mesh-terms=* Aging
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Aqueous Humor
* Blotting, Western
* Cataract
* Cell Survival
* Cells, Cultured
* Enzyme-Linked Immunosorbent Assay
* Epithelial Cells
* Female
* Fluorescent Antibody Technique, Indirect
* Humans
* Hydrogen Peroxide
* Lens, Crystalline
* Male
* Middle Aged
* Oxidants
* Oxidative Stress
* RNA, Messenger
* Real-Time Polymerase Chain Reaction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757856
}}
{{medline-entry
|title=Effects of senescence and angiotensin II on expression and processing of amyloid precursor protein in human cerebral microvascular endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29348391
|abstract=The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein ([[APP]]) in human brain microvascular endothelial cells (BMECs). Senescence caused a decrease in [[APP]] expression thereby resulting in reduced secretion of soluble [[APP]]α (s[[APP]]α). In contrast, β-site [[APP]] cleaving enzyme ([[BACE1]]) expression and production of amyloid β (Aβ)40 were increased in senescent endothelium. Importantly, in senescent human BMECs, treatment with [[BACE1]] inhibitor IV inhibited Aβ generation and increased s[[APP]]α production by enhancing a disintegrin and metalloprotease (ADAM)10 expression. Furthermore, Ang II impaired expression of [[ADAM10]] and significantly reduced generation of s[[APP]]α in senescent human BMECs. This inhibitory effect of Ang II was prevented by treatment with [[BACE1]] inhibitor IV. Our results suggest that impairment of α-processing and shift to amyloidogenic pathway of [[APP]] contribute to endothelial dysfunction induced by senescence. Loss of s[[APP]]α in senescent cells treated with Ang II exacerbates detrimental effects of senescence on [[APP]] processing. Notably, inhibition of [[BACE1]] has beneficial effects on senescence induced endothelial dysfunction. Reported findings may help to explain contributions of senescent cerebral microvascular endothelium to development of cerebral amyloid angiopathy and Alzheimer's disease (AD) pathology.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Angiotensin II
* Aspartic Acid Endopeptidases
* Blotting, Western
* Brain
* Cerebral Amyloid Angiopathy
* Endothelial Cells
* Enzyme-Linked Immunosorbent Assay
* Gene Expression Regulation
* Humans
* Vasoconstrictor Agents
|keywords=* APP processing
* Ang II
* BACE1 inhibitor IV
* endothelium
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811245
}}
{{medline-entry
|title=Disturbances in the control of capillary flow in an aged [[APP]] /PS1ΔE9 model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29131981
|abstract=Vascular changes are thought to contribute to the development of Alzheimer's disease, and both cerebral blood flow and its responses during neural activation are reduced before Alzheimer's disease symptoms onset. One hypothetical explanation is that capillary dysfunction reduces oxygen extraction efficacy. This study compares the morphology and hemodynamics of the microvasculature in the somatosensory cortex of 18-month-old [[APP]] /PS1ΔE9 (transgenic [Tg]) mice and wild-type (WT) littermates. In particular, the extent to which their capillary transit times homogenize during functional activation was measured and compared. Capillary length density was similar in both groups but capillary blood flow during rest was lower in the Tg mice, indicating that cortical oxygen availability is reduced. The capillary hemodynamic response to functional activation was larger, and lasted longer in Tg mice than in WT mice. The homogenization of capillary transit times during functional activation, which we previously demonstrated in young mice, was absent in the Tg mice. This study demonstrates that both neurovascular coupling and capillary function are profoundly disturbed in aged Tg and WT mice.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Blood Flow Velocity
* Capillaries
* Cerebrovascular Circulation
* Disease Models, Animal
* Female
* Hemodynamics
* Mice, Inbred C57BL
* Mice, Transgenic
* Oxygen Consumption
* Somatosensory Cortex
|keywords=* Alzheimer's disease
* Capillary dysfunction
* Capillary length density
* Capillary transit time heterogeneity
* Cerebral blood flow
* Red blood cell velocity
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2017.10.006
}}
{{medline-entry
|title=Istradefylline reduces memory deficits in aging mice with amyloid pathology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29100987
|abstract=Adenosine A  receptors are putative therapeutic targets for neurological disorders. The adenosine A  receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A  receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein ([[APP]]), or amyloid plaques, but not overexpression of [[APP]] per se, increase astrocytic A  receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A  receptor blockers might help counteract memory problems in patients with Alzheimer's disease.
|mesh-terms=* Adenosine A2 Receptor Antagonists
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Astrocytes
* Brain
* Female
* Humans
* Male
* Memory Disorders
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Plaque, Amyloid
* Purines
* Receptor, Adenosine A2A
|keywords=* Adenosine receptors
* Alzheimer's disease
* Amyloid plaques
* Antagonist
* Astrocytes
* Behavior
* Inhibition
* Istradefylline
* Memory
* Therapy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747997
}}
{{medline-entry
|title=The age-related slow increase in amyloid pathology in [[APP]].V717I mice activates microglia, but does not alter hippocampal neurogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29059594
|abstract=In Alzheimer's disease, the hippocampus is characterized by abundant deposition of amyloid peptides (amyloid β [Aβ]) and neuroinflammation. Adult hippocampal neurogenesis (AHN) is a form of plasticity that contributes to cognition and can be influenced by either or both pathology and neuroinflammation. Their interaction has been studied before in rapidly progressing transgenic mouse models with strong overexpression of amyloid precursor protein ([[APP]]) and/or presenilin 1. So far, changes in AHN and neuroinflammation remain poorly characterized in slower progressing models at advanced age, which approach more closely sporadic Alzheimer's disease. Here, we analyzed 10- to 26-month-old [[APP]].V717I mice for possible correlations between Aβ pathology, microglia, and AHN. The age-related increase in amyloid pathology was closely paralleled by microglial [[CD68]] upregulation, which was largely absent in age-matched wild-type littermates. Notably, aging reduced the AHN marker doublecortin, but not calretinin, to a similar extent in wild-type and [[APP]].V717I mice between 10 and 26 months. This demonstrates that AHN is influenced by advanced age in the [[APP]].V717I mouse model, but not by Aβ and microglial activation.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Cognition
* Disease Models, Animal
* Hippocampus
* Mice, Transgenic
* Microglia
* Microtubule-Associated Proteins
* Neurogenesis
* Neuropeptides
* Presenilin-1
|keywords=* APP
* Aging
* Alzheimer's disease
* Calretinin
* Doublecortin
* Neurogenesis
* Neuroinflammation
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2017.09.013
}}
{{medline-entry
|title=Sortilin inhibits amyloid pathology by regulating non-specific degradation of [[APP]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29056359
|abstract=Amyloid plaque is one of the hallmarks of Alzheimer's disease (AD). The key component beta-amyloid (Aβ) is generated via proteolytic processing of amyloid precursor protein ([[APP]]). Sortilin (encoded by the gene Sort1) is a vacuolar protein sorting 10 protein domain-containing receptor, which is up-regulated in the brain of AD, colocalizes with amyloid plaques and interacts with [[APP]]. However, its role in amyloidogenesis remains unclear. In this study, we first found that the protein level of sortilin was up-regulated in the neocortex of aged (7 and 9months old) but not young (2 and 5months old) AD mice ([[APP]]/PS1). 9months old [[APP]]/PS1 transgenic mice with Sort1 gene knockout showed increased amyloid pathology in the brain; and this phenotype was rescued by intrahippocampal injection of AAV-hSORT1. Moreover, the 9months old [[APP]]/PS1 mice without Sort1 also displayed a decreased number of neurons and increased astrocyte activation in the hippocampus. In addition, the present study showed that the intracellular domain of sortilin was involved in the regulation of the non-specific degradation of [[APP]]. Together, our findings indicate that sortilin is a beneficial protein for the reduction of amyloid pathology in [[APP]]/PS1 mice by promoting [[APP]] degradation.
|mesh-terms=* Adaptor Proteins, Vesicular Transport
* Aging
* Amyloid beta-Protein Precursor
* Animals
* Astrocytes
* Cell Count
* Female
* Hippocampus
* Male
* Mice
* Mice, Knockout
* Mice, Transgenic
* Neocortex
* Neurons
* Plaque, Amyloid
* Primary Cell Culture
|keywords=* APP
* Amyloid production
* Degradation
* Sortilin
|full-text-url=https://sci-hub.do/10.1016/j.expneurol.2017.10.018
}}
{{medline-entry
|title=Differential deregulation of [[NGF]] and [[BDNF]] neurotrophins in a transgenic rat model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28865749
|abstract=Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor ([[NGF]]) and brain-derived neurotrophic factor ([[BDNF]]) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-[[APP]] transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of [[NGF]] and [[BDNF]] transcripts and protein expression. While [[BDNF]] mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in [[NGF]] mRNA expression even at advanced stages. Paradoxically, the protein levels of the [[NGF]] precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of [[NGF]] were evident in McGill transgenic rats, in line with the paradoxical upregulation of pro[[NGF]], as seen in Alzheimer's disease, in the absence of changes in [[NGF]] mRNA. The compromise in [[NGF]] metabolism and [[BDNF]] levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of [[NGF]] and [[BDNF]] neurotrophins, whereby deficits in [[BDNF]] mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in [[NGF]] metabolism and cholinergic synapse loss manifest.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Blotting, Western
* Brain
* Brain-Derived Neurotrophic Factor
* Disease Models, Animal
* Disease Progression
* Female
* Gene Expression Regulation
* Humans
* Immunohistochemistry
* Male
* Matrix Metalloproteinase 9
* Nerve Growth Factor
* Neurons
* Plaque, Amyloid
* RNA, Messenger
* Rats, Transgenic
|keywords=* Alzheimer's disease
* Amyloid-β
* BDNF
* Cholinergic
* MMP-9
* Nerve growth factor
* Neuroserpin
* Neurotrophins
* Synaptic plasticity
* proNGF
* tPA
|full-text-url=https://sci-hub.do/10.1016/j.nbd.2017.08.019
}}
{{medline-entry
|title=Analyzing Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Aging and Vascular Amyloid Pathology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28824611
|abstract=In aging individuals, both protective as well as regulatory immune functions are declining, resulting in an increased susceptibility to infections as well as to autoimmunity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2-deficiency in immune cell subsets has been shown to be associated with aging. Using intravital marker-free NAD(P)H-fluorescence lifetime imaging, we have previously identified microglia/myeloid cells and astrocytes as main cellular sources of NADPH oxidase (NOX) activity in the CNS during neuroinflammation, due to an overactivation of NOX. The overactivated NOX enzymes catalyze the massive production of the highly reactive [Formula: see text] which initiates in a chain reaction the overproduction of diverse reactive oxygen species (ROS). Age-dependent oxidative distress levels in the brain and their cellular sources are not known. Furthermore, it is unclear whether in age-dependent diseases oxidative distress is initiated by overproduction of ROS or by a decrease in antioxidant capacity, subsequently leading to neurodegeneration in the CNS. Here, we compare the activation level of NOX enzymes in the cerebral cortex of young and aged mice as well as in a model of vascular amyloid pathology. Despite the fact that a striking change in the morphology of microglia can be detected between young and aged individuals, we find comparable low-level NOX activation both in young and old mice. In contrast, aged mice with the human [[APP]]  mutation, a model for cerebral amyloid angiopathy (CAA), displayed increased focal NOX overactivation in the brain cortex, especially in tissue areas around the vessels. Despite activated morphology in microglia, NOX overactivation was detected only in a small fraction of these cells, in contrast to other pathologies with overt inflammation as experimental autoimmune encephalomyelitis (EAE) or glioblastoma. Similar to these pathologies, the astrocytes majorly contribute to the NOX overactivation in the brain cortex during CAA. Together, these findings emphasize the role of other cellular sources of activated NOX than phagocytes not only during EAE but also in models of amyloid pathology. Moreover, they may strengthen the hypothesis that microglia/monocytes show a diminished potential for clearance of amyloid beta protein.

|keywords=* Alzheimer’s disease
* NADPH oxidases
* aging
* astrocytes
* cerebral amyloid angiopathy
* microglia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534478
}}
{{medline-entry
|title=Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A  in a spatial-specific manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28750656
|abstract=Alzheimer's disease (AD) is histopathologically characterized by the build-up of fibrillar amyloid beta (Aβ) in the form of amyloid plaques and the development of intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated Tau. Although amyloid fibrils were originally considered responsible for AD pathogenesis, recent convincing evidence strongly implicates soluble oligomeric Aβ as the primary neurotoxic species driving disease progression. A third largely ignored pathological hallmark, originally described by Alois Alzheimer, is the presence of "adipose inclusions", suggestive of aberrant lipid metabolism. The molecular mechanisms underlying these "lipoid granules", as well as their potential link to soluble and/or fibrillar Aβ remain largely unknown. Seeking to better-understand these conundrums, we took advantage of the powerful technology of multidimensional mass spectrometry-based shotgun lipidomics and an AD transgenic mouse model overexpressing mutant amyloid precursor protein ([[APP]] E693Δ-Osaka-), where AD-like pathology and neurodegeneration occur as a consequence of oligomeric Aβ accumulation in the absence of amyloid plaques. Our results revealed for the first time that [[APP]] overexpression and oligomeric Aβ accumulation lead to an additive global accumulation of nonesterified polyunsaturated fatty acids (PUFAs) independently of amyloid plaques. Furthermore, we revealed that this accumulation is mediated by an increase in phospholipase A  (PLA ) activity, evidenced by an accumulation of sn-1 lysophosphatidylcholine and by MAPK-mediated phosphorylation/activation of group IV Ca -dependent cytosolic (cPLA ) and the group VI Ca -independent PLA  (iPLA ) independently of PKC. We further revealed that Aβ-induced oxidative stress also disrupts lipid metabolism via reactive oxygen species-mediated phospholipid cleavage leading to increased sn-2 lysophosphatidylcholine as well as lipid peroxidation and the subsequent accumulation of 4-hydroxynonenal. Brain histological studies implicated cPLA  activity with arachidonic acid accumulation within myelin-rich regions, and iPLA  activity with docosahexaenoic acid accumulation within pyramidal neuron-rich regions. Taken together, our results suggest that PLA -mediated accumulation of free PUFAs drives AD-related disruption of brain lipid metabolism.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Cytosol
* Disease Models, Animal
* Extracellular Signal-Regulated MAP Kinases
* Fatty Acids, Unsaturated
* Humans
* Mice, Transgenic
* Phospholipases A2, Calcium-Independent
* Phosphorylation
* Plaque, Amyloid
* Protein Kinase C
|keywords=* Alzheimer’s disease
* Amyloid-beta
* Fatty acid
* Lysophospholipid
* Oxidative stress
* Phospholipase A2
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530945
}}
{{medline-entry
|title=Proteins Involved in Endocytosis Are Upregulated by Ageing in the Normal Human Brain: Implications for the Development of Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28655199
|abstract=The greatest risk factor for Alzheimer's disease (AD) is advanced age, but the reason for this association remains unclear. Amyloid-β (Aβ) is produced from amyloid precursor protein ([[APP]]) primarily after [[APP]] is internalized by clathrin-mediated or clathrin-independent endocytosis. Changes in endocytosis in AD have been identified. We hypothesized that endocytic protein expression is altered during ageing, thus influencing the likelihood of developing AD by increasing Aβ production. We explored how levels of endocytic proteins, [[APP]], its metabolites, secretase enzymes, and tau varied with age in cortical brain samples from men of three age ranges (young [20-30], middle aged [45-55], and old [70-90]) with no symptoms of dementia. Aβ40 and Aβ42 were significantly increased in old brains, while [[APP]] and secretase expression was unaffected by age. Phosphorylated GSK3β increased significantly with age, a possible precursor for neurofibrillary tangle production, although phosphorylated tau was undetectable. Significant increases in clathrin, dynamin-1, AP180, Rab-5, caveolin-2, and flotillin-2 were seen in old brains. Rab-5 also increased in middle-aged brains prior to changes in Aβ levels. This age-related increase in endocytic protein expression, not described previously, suggests an age-related upregulation of endocytosis which could predispose older individuals to develop AD by increasing [[APP]] internalization and Aβ generation.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Brain
* Caveolin 2
* Clathrin
* Dynamin I
* Endocytosis
* Humans
* Male
* Membrane Proteins
* Middle Aged
* Monomeric Clathrin Assembly Proteins
* Risk Factors
* Up-Regulation
* Vesicular Transport Proteins
* tau Proteins

|full-text-url=https://sci-hub.do/10.1093/gerona/glx135
}}
{{medline-entry
|title=Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28647555
|abstract=The intellectual disability that characterizes Down syndrome (DS) is primarily caused by prenatal changes in central nervous system growth and differentiation. However, in later life stages, the cognitive abilities of DS individuals progressively decline due to accelerated aging and the development of Alzheimer's disease (AD) neuropathology. The AD neuropathology in DS has been related to the overexpression of several genes encoded by Hsa21 including [[DYRK1A]] (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), which encodes a protein kinase that performs crucial functions in the regulation of multiple signaling pathways that contribute to normal brain development and adult brain physiology. Studies performed in vitro and in vivo in animal models overexpressing this gene have demonstrated that the [[DYRK1A]] gene also plays a crucial role in several neurodegenerative processes found in DS. The Ts65Dn (TS) mouse bears a partial triplication of several Hsa21 orthologous genes, including Dyrk1A, and replicates many DS-like abnormalities, including age-dependent cognitive decline, cholinergic neuron degeneration, increased levels of [[APP]] and Aβ, and tau hyperphosphorylation. To use a more direct approach to evaluate the role of the gene dosage of Dyrk1A on the neurodegenerative profile of this model, TS mice were crossed with Dyrk1A KO mice to obtain mice with a triplication of a segment of Mmu16 that includes this gene, mice that are trisomic for the same genes but only carry two copies of Dyrk1A, euploid mice with a normal Dyrk1A dosage, and CO animals with a single copy of Dyrk1A. Normalizing the gene dosage of Dyrk1A in the TS mouse rescued the density of senescent cells in the cingulate cortex, hippocampus and septum, prevented cholinergic neuron degeneration, and reduced App expression in the hippocampus, Aβ load in the cortex and hippocampus, the expression of phosphorylated tau at the Ser202 residue in the hippocampus and cerebellum and the levels of total tau in the cortex, hippocampus and cerebellum. Thus, the present study provides further support for the role of the Dyrk1A gene in several AD-like phenotypes found in TS mice and indicates that this gene could be a therapeutic target to treat AD in DS.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Cholinergic Neurons
* Disease Models, Animal
* Down Syndrome
* Gene Dosage
* Male
* Mice, 129 Strain
* Mice, Inbred C3H
* Mice, Inbred C57BL
* Mice, Transgenic
* Nerve Degeneration
* Peptide Fragments
* Phenotype
* Phosphorylation
* Protein-Serine-Threonine Kinases
* Protein-Tyrosine Kinases
* tau Proteins
|keywords=* APP
* Down syndrome
* Dyrk1A
* Neurodegeneration
* Senescence
* Tau
* Ts65Dn
|full-text-url=https://sci-hub.do/10.1016/j.nbd.2017.06.010
}}
{{medline-entry
|title=Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in [[APP]] (swe)/PS1 (ΔE9) mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28597477
|abstract=Alzheimer's disease (AD), a progressive development dementia, is increasingly impacting patients' living conditions worldwide. Despite medical care and funding support, there are still no highly individualized drugs and practical strategies for clinical prevention and treatment. Developmentally regulated brain protein (abbreviated as Drebrin or Dbn, also known as Dbn1 in mouse) exists in neurons, especially in dendrites, and is an actin-binding protein that modulates synaptic morphology and long-term memory. However, the majority of previous studies have focused on its upstream proteins and neglected the impact Drebrin has on behavior and AD in vivo. Here, we tracked the behavioral performances of 4-, 8-, 12-, and 16-month-old AD mice and investigated the expression level of Drebrin in their hippocampi. A Pearson correlation analysis between Drebrin levels and behavioral data was performed. Subsequently, 2-month-old AD mice were injected with rAAV-zsGreen-Dbn1 vector, composing the [[APP]]/PS1-Dbn1 group, and sex- and age-matched AD mice were injected with rAAV-tdTomato vector to serve as the control group. All mice were conducted behavioral tests and molecular detection 6 months later. (i) The expression of Drebrin is decreased in the hippocampus of aged AD mice compared with that of age-matched WT and young adult AD mice; (ii) cognitive ability of [[APP]]/PS1 mice decreases with age; (iii) Drebrin protein expression in the hippocampus correlates with behavioral performance in different aged AD mice; (iv) cognitive ability improved significantly in [[APP]]/PS1-Dbn1 mice; (v) the expression level of Drebrin in [[APP]]/PS1-Dbn1 mouse hippocampus was significantly increased; (vi) the pathological lesion of AD was alleviated in [[APP]]/PS1-Dbn1 mice; (vii) the filamentous actin (F-actin) and microtubule-associated protein 2(MAP-2) in [[APP]]/PS1-Dbn1 mice were notably more than control mice. In this study, an effective expression of Drebrin improves cognitive abilities and alleviates lesions in an AD mouse model. These results may provide some valid resources for therapy and research of AD.
|mesh-terms=* Actins
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Cognition
* Disease Models, Animal
* Down-Regulation
* Female
* Genetic Vectors
* Hippocampus
* Humans
* Mice, Inbred C57BL
* Mice, Transgenic
* Microtubule-Associated Proteins
* Neuropeptides
* Presenilin-1
|keywords=* APP (swe)/PS1 (ΔE9) mice
* Alzheimer's disease
* Drebrin
* behavior
* hippocampus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492767
}}
{{medline-entry
|title=Neuronal tetraploidization in the cerebral cortex correlates with reduced cognition in mice and precedes and recapitulates Alzheimer's-associated neuropathology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28494436
|abstract=A controversy exists as to whether de novo-generated neuronal tetraploidy (dnNT) occurs in Alzheimer's disease. In addition, the presence of age-associated dnNT in the normal brain remains unexplored. Here we show that age-associated dnNT occurs in both superficial and deep layers of the cerebral cortex of adult mice, a process that is blocked in the absence of [[E2F1]], a known regulator of cell cycle progression. This blockage correlates with improved cognition despite compromised neurogenesis in the adult hippocampus was confirmed in mice lacking the E2f1 gene. We also show that the human cerebral cortex contains tetraploid neurons. In normal humans, age-associated dnNT specifically occurs in the entorhinal cortex whereas, in Alzheimer, dnNT also affects association cortices prior to neurofibrillary tangle formation. Alzheimer-associated dnNT is likely potentiated by altered amyloid precursor protein ([[APP]]) processing as it is enhanced in the cerebral cortex of young [[APP]] /PS1  mice, long before the first amyloid plaques are visible in their brains. In contrast to age-associated dnNT, enhanced dnNT in [[APP]] /PS1  mice mostly affects the superficial cortical layers. The correlation of dnNT with reduced cognition in mice and its spatiotemporal course, preceding and recapitulating Alzheimer-associated neuropathology, makes this process a potential target for intervention in Alzheimer's disease.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Cell Cycle
* Cerebral Cortex
* Cognition
* E2F1 Transcription Factor
* Female
* Hippocampus
* Humans
* Male
* Mice, Transgenic
* Middle Aged
* Neurofibrillary Tangles
* Neurogenesis
* Neurons
* Tetraploidy
|keywords=* DNA content
* E2F1
* FISH
* Flow cytometry
* Memory
* β-Amyloid
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2017.04.008
}}
{{medline-entry
|title=Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged [[APP]] /PS1  transgenic mice: Effect of long-term treatment with paroxetine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28461249
|abstract=Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of [[APP]] /PS1  transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis, and spontaneous alternation behaviour, a measure of spatial working memory, in transgenic mice. We observed no difference in granular neurons between transgenic and wild type mice up till 18months of age, and no differences with age in wild type mice. The number of neuroblasts and the performance in the spontaneous alternation task was reduced in aged transgenic mice. Paroxetine treatment from 9 to 18months of age reduced hippocampal amyloidosis without affecting the number of neuroblasts or granular neurons. These findings suggest that the amyloidosis affects the differentiation of neuroblasts and spatial working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Bromodeoxyuridine
* Cytochrome P-450 CYP2D6 Inhibitors
* Dentate Gyrus
* Disease Models, Animal
* Exploratory Behavior
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microtubule-Associated Proteins
* Mutation
* Neural Stem Cells
* Neurogenesis
* Neurons
* Neuropeptides
* Paroxetine
* Presenilin-1
|keywords=* APP/PS1 mice
* Amyloid plaque load
* Granule cells
* Hippocampus
* Neurogenesis
* Paroxetine
* SSRI
* Spontaneous alternation behaviour
|full-text-url=https://sci-hub.do/10.1016/j.nbd.2017.04.021
}}
{{medline-entry
|title=Amyloid precursor protein, lipofuscin accumulation and expression of autophagy markers in aged bovine brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28407771
|abstract=Autophagy is a highly regulated process involving the bulk degradation of cytoplasmic macromolecules and organelles in mammalian cells via the lysosomal system. Dysregulation of autophagy is implicated in the pathogenesis of many neurodegenerative diseases and integrity of the autophagosomal - lysosomal network appears to be critical in the progression of aging. Our aim was to survey the expression of autophagy markers and Amyloid precursor protein ([[APP]]) in aged bovine brains. For our study, we collected samples from the brain of old (aged 11-20 years) and young (aged 1-5 years) Podolic dairy cows. Formalin-fixed and paraffin embedded sections were stained with routine and special staining techniques. Primary antibodies for [[APP]] and autophagy markers such as Beclin-1 and LC3 were used to perform immunofluorescence and Western blot analysis. Histologically, the most consistent morphological finding was the age-related accumulation of intraneuronal lipofuscin. Furthermore, in aged bovine brains, immunofluorescence detected a strongly positive immunoreaction to [[APP]] and LC3. Beclin-1 immunoreaction was weak or absent. In young controls, the immunoreaction for Beclin-1 and LC3 was mild while the immunoreaction for [[APP]] was absent. Western blot analysis confirmed an increased [[APP]] expression and LC3-II/LC3-I ratio and a decreased expression of Beclin-1 in aged cows. These data suggest that, in aged bovine, autophagy is significantly impaired if compared to young animals and they confirm that intraneuronal [[APP]] deposition increases with age.
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Animals
* Autophagy
* Beclin-1
* Biomarkers
* Blotting, Western
* Brain
* Cattle
* Female
* Lipofuscin
* Membrane Proteins
|keywords=* Ageing
* Autophagy
* Bovine
* Brain
* Neuropathology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390414
}}
{{medline-entry
|title=Effects of vitamin D and resveratrol on metabolic associated markers in liver and adipose tissue from SAMP8 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28411010
|abstract=SAMP8 mice exhibit multiple metabolic characteristics associated with age, and it is a suitable candidate for researching aging associated metabolic dysfunction. We aimed to 1) explore how key metabolic markers will be altered in both liver and adipose tissue with aging in SAMP8 mice; and 2) how the combination of vitamin D (VD) with resveratrol (RSV) will affect aging associated metabolic impairment in liver and adipose tissue from SAMP8 mice. SAMP8 mice and their control SAMR1 mice were divided into 5 groups, i.e. SAMR1, SAMP8, SAMP8 mice supplemented with VD, RSV and VD combined with RSV group, respectively. At the end of the intervention, glucose and insulin tolerance, p-AMP-activated protein kinase (AMPK) and amyloid precursor protein ([[APP]]), and endoplasmic reticulum (ER) stress markers in liver and adipose tissue, adiponectin secretion, p-NF-κBp65 and [[TNF]]-α protein expression in adipose tissue were determined. Compared to SAMR1 control, SAMP8 mice demonstrate impaired glucose tolerance and reduction in circulating adiponectin level; in the liver, SAMP8 mice have reduction in p-Aktser473, elevation in PTP1B and [[APP]], p-eIF2α, GRP78 and p-JNK protein expression. In epididymal (EPI) fat, SAMP8 mice also have elevated p-Aktser473 and PTP1B compared to SAMR1 mice. In both epididymal (EPI) and subcutaneous (SC) fat, there were elevated ER stress markers, reduced p-AMPK and elevated [[APP]], as well as elevated p-NF-κBp65 and [[TNF]]-α protein expression from SAMP8 compared to SAMR1 mice. In liver, the combined intervention significantly restored p-Aktser473, p-eIF2α and p-JNK protein expression. In both EPI and SC fat, the combined intervention is effective for reducing p-NF-κB p65 and [[TNF]]-α in both fat depot, while only partially reduced ER stress markers in SC fat. As for adiponectin, their combination is unable to reverse reduction in adiponectin level. Adiponectin secretion in SC fat from VD, RSV and VDRSV group were also significantly reduced compared to SAMR1. The combined intervention might exert greater beneficial effects for reversing aging associated metabolic dysfunction in liver and adipose tissue from SAMP8 mice.
|mesh-terms=* Adipose Tissue
* Aging
* Animals
* Anti-Inflammatory Agents, Non-Steroidal
* Biomarkers
* Blood Glucose
* Body Weight
* Drug Combinations
* Drug Evaluation, Preclinical
* Endoplasmic Reticulum Stress
* Glucose Tolerance Test
* Insulin Resistance
* Liver
* Male
* Mice, Mutant Strains
* Organ Size
* Oxidative Stress
* Resveratrol
* Stilbenes
* Vitamin D
|keywords=* Adiponectin
* Endoplasmic reticulum stress
* Inflammation
* Insulin resistance
* Resveratrol
* Vitamin D
|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.03.017
}}
{{medline-entry
|title=Effect of aging and Alzheimer's disease-like pathology on brain monoamines in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28414094
|abstract=Aging is the greatest single risk factor of the neurodegenerative disorder Alzheimer's disease (AD). The monoaminergic system, including serotonin (5-HT), dopamine (DA) and noradrenaline (NA) modulates cognition, which is affected in AD. Changes in monoamine levels have been observed in AD, but these can both be age- and/or disease-related. We examined whether brain monoamine levels change as part of physiological aging and/or AD-like disease in [[APP]] /PS1  ([[APP]]/PS1) transgenic mice. The neocortex, hippocampus, striatum, brainstem and cerebellum of 6-, 12-, 18- and 24-month-old B6C3 wild-type (WT) mice and of 18-month old [[APP]]/PS1 and WT mice were analysed for 5-HT, DA and NA contents by high pressure liquid chromatography (HPLC), along with neocortex from 14-month-old [[APP]]/PS1 and WT mice. While, we observed no aging effect in WT mice, we detected region-specific changes in the levels of all monoamines in 18-month-old transgenic compared with WT mice. This included reductions in 5-HT (-30%), DA (-47%) and NA (-32%) levels in the neocortex and increases of 5-HT in the brainstem ( 18%). No changes were observed in any of the monoamines in the neocortex from 14-month-old [[APP]]/PS1 mice. In combination, these findings indicate that aging alone is not sufficient to affect brain monoamine levels, unlike the [[APP]] /PS1  genotype.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Biogenic Monoamines
* Brain
* Male
* Mice
* Mice, Inbred C3H
* Mice, Inbred C57BL
* Mice, Transgenic
* Presenilin-1
|keywords=* Amyloid precursor protein/presenilin 1
* Brainstem
* Dopamine
* Dopamine (PubChem CID: 681)
* Neocortex
* Noradrenaline
* Noradrenaline (PubChem CID: 439260)
* Serotonin
* Serotonin (PubChem CID: 5202)
|full-text-url=https://sci-hub.do/10.1016/j.neuint.2017.04.008
}}
{{medline-entry
|title=Regulation of Alpha-Secretase [[ADAM10]] [i]In vitro[/i] and [i]In vivo[/i]: Genetic, Epigenetic, and Protein-Based Mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28367112
|abstract=[[ADAM10]] (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving [[APP]] in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective [[APP]]-derived fragment, [[APP]]s-alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in [[ADAM10]] activity shifts the balance of [[APP]] processing toward [[APP]]s-alpha and protects the brain from amyloid deposition and disease. Thus, increasing [[ADAM10]] activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating [[ADAM10]] expression. Therefore, in this article, we will (1) review reports on the physiological regulation of [[ADAM10]] at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change [[ADAM10]] expression [i]in vitro[/i] and [i]in vivo[/i], (3) report how neuronal [[ADAM10]] expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of [[ADAM10]] may help to preserve or restore brain function.

|keywords=* ADAM10
* Alzheimer's disease
* aging
* alpha-secretase
* mouse models
* promoter
* spine
* transcription factors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355436
}}
{{medline-entry
|title=Knockdown of [[APP]]L mimics transgenic Aβ induced neurodegenerative phenotypes in Drosophila.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28336338
|abstract=A variety of Drosophila mutant lines have been established as potential disease-models to study various disease mechanisms including human neurodegenerative diseases like Alzheimer's disease (AD), Huntington's disease (HD) and Parkinson's disease (PD). The evolutionary conservation of [[APP]] (Amyloid Precursor Protein) and [[APP]]L (Amyloid Precursor Protein-Like) and the comparable detrimental effects caused by their metabolic products strongly implies the conservation of their normal physiological functions. In view of this milieu, a comparative analysis on the pattern of neurodegenerative phenotypes between Drosophila [[APP]]L-RNAi line and transgenic Drosophila line expressing eye tissue specific human Aβ (Amyloid beta) was undertaken. Our results clearly show that Drosophila [[APP]]L-RNAi largely mimics transgenic Aβ in various phenotypes which include eye degeneration, reduced longevity and motor neuron deficit functions, etc. The ultra-structural morphological pattern of eye degeneration was confirmed by scanning electron microscopy. Further, a comparative study on longevity and motor behaviour between Aβ expressing and [[APP]]L knockdown lines revealed similar kind of behavioural deficit and longevity phenotypes. Therefore, it is suggested that [[APP]]L-knockdown approach can be used as an alternative approach to study neurodegenerative diseases in the fly model. To the best of our knowledge this is the first report showing comparable phenotypes between [[APP]]L and Aβ in AD model of Drosophila.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Animals, Genetically Modified
* Disease Models, Animal
* Drosophila
* Drosophila Proteins
* Eye
* Gene Knockdown Techniques
* Humans
* Membrane Proteins
* Motor Activity
* Motor Neurons
* Nerve Tissue Proteins
* Neurodegenerative Diseases
* Phenotype
* Survival Analysis
|keywords=* APP
* APPL-RNAi
* Alzheimer's disease
* Drosophila
* Eye degeneration
* Longevity
* Motor neuron function
* SEM
|full-text-url=https://sci-hub.do/10.1016/j.neulet.2017.03.030
}}
{{medline-entry
|title=Nonamyloidogenic processing of amyloid beta precursor protein is associated with retinal function improvement in aging male [[APP]] /PS1ΔE9 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28262325
|abstract=Vision declines during normal aging and in Alzheimer's disease (AD). Although the toxic role of amyloid beta (Aβ) has been established in AD pathogenesis, its influence on the aging retina is unclear. Using [[APP]] /PS1ΔE9 transgenic ([[TG]]) mice, a classical AD model, the retinal cell function and survival was assessed by electroretinogram ([[ERG]]) recordings and immunofluorescent stainings. Strikingly, photopic [[ERG]] measurements revealed that the retinal response mediated by cones was preserved in aging [[TG]] mice relative to WT controls. In contrast to the cortex, the expression of mutated [[APP]]  and PS1ΔE9 did not allow to detect Aβ or amyloid plaques in 13-month-old male [[TG]] retinae. In addition, the CTFβ/CTFα ratio was significantly lower in retinal samples than that in cortical extracts, suggesting that the nonamyloidogenic pathway may endogenously limit Aβ formation in the retina of male mice. Collectively, our data suggest that retinal-specific processing of amyloid may confer protection against AD and selectively preserve cone-dependent vision during aging.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Cell Survival
* Color Vision
* Disease Models, Animal
* Electroretinography
* Fluorescent Antibody Technique
* Male
* Mice, Transgenic
* Retina
* Retinal Cone Photoreceptor Cells
|keywords=* Aging
* Alzheimer's disease
* Color vision
* Electroretinogram
* Photoreceptors
* Retina
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2017.02.004
}}
{{medline-entry
|title=Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28212403
|abstract=Hydrocephalus is a complex neurological disorder with a pervasive impact on the central nervous system. Previous work has demonstrated derangements in the biochemical profile of cerebrospinal fluid (CSF) in hydrocephalus, particularly in infants and children, in whom neurodevelopment is progressing in parallel with concomitant neurological injury. The objective of this study was to examine the CSF of children with congenital hydrocephalus (CHC) to gain insight into the pathophysiology of hydrocephalus and identify candidate biomarkers of CHC with potential diagnostic and therapeutic value. CSF levels of amyloid precursor protein ([[APP]]) and derivative isoforms (s[[APP]]α, s[[APP]]β, Aβ42), tau, phosphorylated tau (pTau), [[L1CAM]], NCAM-1, aquaporin 4 ([[AQP4]]), and total protein (TP) were measured by ELISA in 20 children with CHC. Two comparative groups were included: age-matched controls and children with other neurological diseases. Demographic parameters, ventricular frontal-occipital horn ratio, associated brain malformations, genetic alterations, and surgical treatments were recorded. Logistic regression analysis and receiver operating characteristic curves were used to examine the association of each CSF protein with CHC. CSF levels of [[APP]], s[[APP]]α, s[[APP]]β, Aβ42, tau, pTau, [[L1CAM]], and NCAM-1 but not [[AQP4]] or TP were increased in untreated CHC. CSF TP and normalized [[L1CAM]] levels were associated with FOR in CHC subjects, while normalized CSF tau levels were associated with FOR in control subjects. Predictive ability for CHC was strongest for s[[APP]]α, especially in subjects ≤12 months of age (p<0.0001 and AUC = 0.99), followed by normalized s[[APP]]β (p = 0.0001, AUC = 0.95), tau, [[APP]], and [[L1CAM]]. Among subjects ≤12 months, a normalized CSF s[[APP]]α cut-point of 0.41 provided the best prediction of CHC (odds ratio = 528, sensitivity = 0.94, specificity = 0.97); these infants were 32 times more likely to have CHC. CSF proteins such as s[[APP]]α and related proteins hold promise as biomarkers of CHC in infants and young children, and provide insight into the pathophysiology of CHC during this critical period in neurodevelopment.
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Biomarkers
* Child
* Female
* Humans
* Hydrocephalus
* Infant
* Infant, Newborn
* Male

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315300
}}
{{medline-entry
|title=[[APP]] Deletion Accounts for Age-Dependent Changes in the Bioenergetic Metabolism and in Hyperphosphorylated CaMKII at Stimulated Hippocampal Presynaptic Active Zones.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28163681
|abstract=Synaptic release sites are characterized by exocytosis-competent synaptic vesicles tightly anchored to the presynaptic active zone (PAZ) whose proteome orchestrates the fast signaling events involved in synaptic vesicle cycle and plasticity. Allocation of the amyloid precursor protein ([[APP]]) to the PAZ proteome implicated a functional impact of [[APP]] in neuronal communication. In this study, we combined state-of-the-art proteomics, electrophysiology and bioinformatics to address protein abundance and functional changes at the native hippocampal PAZ in young and old [[APP]]-KO mice. We evaluated if [[APP]] deletion has an impact on the metabolic activity of presynaptic mitochondria. Furthermore, we quantified differences in the phosphorylation status after long-term-potentiation (LTP) induction at the purified native PAZ. We observed an increase in the phosphorylation of the signaling enzyme calmodulin-dependent kinase II (CaMKII) only in old [[APP]]-KO mice. During aging [[APP]] deletion is accompanied by a severe decrease in metabolic activity and hyperphosphorylation of CaMKII. This attributes an essential functional role to [[APP]] at hippocampal PAZ and putative molecular mechanisms underlying the age-dependent impairments in learning and memory in [[APP]]-KO mice.

|keywords=* LTP
* aging
* amyloid precursor protein
* hippocampus
* mitochondria
* presynaptic active zone
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247443
}}
{{medline-entry
|title=Mid-life environmental enrichment increases synaptic density in [[CA1]] in a mouse model of Aβ-associated pathology and positively influences synaptic and cognitive health in healthy ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27987205
|abstract=Early-life cognitive enrichment may reduce the risk of experiencing cognitive deterioration and dementia in later-life. However, an intervention to prevent or delay dementia is likely to be taken up in mid to later-life. Hence, we investigated the effects of environmental enrichment in wildtype mice and in a mouse model of Aβ neuropathology ([[APP]]  /PS1  ) from 6 months of age. After 6 months of housing in standard laboratory cages, [[APP]]  /PS1  (n = 27) and healthy wildtype (n = 21) mice were randomly assigned to either enriched or standard housing. At 12 months of age, wildtype mice showed altered synaptic protein levels and relatively superior cognitive performance afforded by environmental enrichment. Environmental enrichment was not associated with alterations to Aβ plaque pathology in the neocortex or hippocampus of [[APP]]  /PS1  mice. However, a significant increase in synaptophysin immunolabeled puncta in the hippocampal subregion, [[CA1]], in [[APP]]  /PS1  mice was detected, with no significant synaptic density changes observed in [[CA3]], or the Fr2 region of the prefrontal cortex. Moreover, a significant increase in hippocampal [[BDNF]] was detected in [[APP]]  /PS1  mice exposed to EE, however, no changes were detected in neocortex or between Wt animals. These results demonstrate that mid to later-life cognitive enrichment has the potential to promote synaptic and cognitive health in ageing, and to enhance compensatory capacity for synaptic connectivity in pathological ageing associated with Aβ deposition.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Blotting, Western
* CA1 Region, Hippocampal
* Cognition Disorders
* Disease Models, Animal
* Enzyme-Linked Immunosorbent Assay
* Housing, Animal
* Image Processing, Computer-Assisted
* Male
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Random Allocation
* Synapses
|keywords=* Alzheimer's disease
* Aβ
* RRID: SCR_002865
* RRID:AB_1860491
* RRID:AB_2263126
* RRID:AB_2278725
* RRID:AB_262185
* RRID:AB_303248
* RRID:AB_476743
* RRID:AB_570874
* RRID:AB_630940
* RRID:MGI_3665286
* RRID:SCR_002668
* RRID:SCR_003070
* brain-derived neurotrophic factor
* cognitive function
* environmental enrichment
* transgenic mouse
|full-text-url=https://sci-hub.do/10.1002/cne.24156
}}
{{medline-entry
|title=Copper accumulation in rodent brain astrocytes: A species difference.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27908425
|abstract=Changes in Cu homeostasis have been implicated in multiple neurodegenerative diseases. Factors controlling and regulating the distribution of Cu in the brain remain largely unknown. We have previously reported that a sub-set of astrocytes in the subventricular zone (SVZ) contain Cu-rich aggregates. Here we expand previous studies with detailed X-ray fluorescent imaging (XRF) analysis of the additional brain areas of hippocampus ([[HP]]) and rostral migratory stream (RMS). We also use conventional DAB (3,3'-diaminobenzidine) staining which accesses both peroxidase and pseudo-peroxidase activities. Both the [[HP]] and RMS support neurogenesis while the latter also serves as a migratory pathway for neuronal precursors. Some variations in neurogenic activities have been noticed between species (such as mice and rats). We report here that in rats, the [[HP]], rostral migratory stream (RMS) and third ventricle contain glia which stain positively for DAB and contain copper-rich aggregates as measured by XRF. In contrast, mice hippocampi and RMS display neither DAB  aggregates nor Cu-rich accumulations via XRF. DAB  aggregates were not induced in the [[HP]] of mice transgenic for human amyloid precursor protein ([[APP]]) and presenilin, suggesting that accumulations positively stained for DAB are not directly caused by [[APP]]. These observed critical differences suggest different properties of the astrocytes in two species. Results suggest that the rat model may have important advantages over the mouse model for the study of hippocampal aging and neurodegeneration.
|mesh-terms=* Animals
* Astrocytes
* Brain
* Copper
* Fluorescence
* Male
* Molecular Imaging
* Rats
* Rats, Sprague-Dawley
* Species Specificity
* X-Rays
|keywords=* Alzheimer’s
* Gomori-positive glia
* Hippocampal aging
* Neurogenesis
* X-ray fluorescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141684
}}
{{medline-entry
|title=The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old [[APP]]/PS1 Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27852778
|abstract=Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving [[APP]] /PS1  transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young [[APP]]/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older [[APP]]/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections between high insulin and extracellular Aβ, but these mechanisms presume that peripheral high insulin elevates brain insulin significantly. We found that physiological hyperinsulinemia in awake, behaving mice does not increase CNS insulin to an appreciable level yet modestly increases extracellular Aβ. We also found that the brain of aged [[APP]]/PS1 mice was not insulin resistant, contrary to the current state of the literature. These results further elucidate the relationship between insulin, the brain, and AD and its conflicting roles as both a risk factor and potential treatment.
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Female
* Hippocampus
* Hyperinsulinism
* Insulin
* Insulin Resistance
* Male
* Mice
* Mice, Transgenic
* Muscle, Skeletal
* Presenilin-1
* Signal Transduction
|keywords=* APP/PS1
* amyloid-beta
* hyperinsulinemic-euglycemic clamps
* insulin
* insulin receptor signaling
* microdialysis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125227
}}
{{medline-entry
|title=Disordered [[APP]] metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27829172
|abstract=Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of neurovascular function.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Brain
* Brain Injuries, Traumatic
* Humans
* Neurovascular Coupling
* Risk Factors
* tau Proteins
|keywords=* Aging
* Alzheimer’s disease
* Amyloid-beta
* Brain trauma
* Neurodegeneration
* Neurovascular unit
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315701
}}
{{medline-entry
|title=Prevention of tau increase in cerebrospinal fluid of [[APP]] transgenic mice suggests downstream effect of [[BACE1]] inhibition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27750032
|abstract=The inhibition of the β-site amyloid precursor protein-cleaving enzyme 1 ([[BACE1]]) is a main therapeutic approach for the treatment of Alzheimer's disease (AD). We previously reported an age-related increase of tau protein in the cerebrospinal fluid (CSF) of amyloid β (Aβ) precursor protein ([[APP]]) transgenic mice. [[APP]] transgenic mice were treated with a potent [[BACE1]] inhibitor. CSF tau and CSF Aβ levels were assessed. A novel high-sensitivity tau sandwich immunoassay was developed. We demonstrate that long-term [[BACE1]] inhibition prevents CSF tau increase both in early-depositing [[APP]] transgenic mice and [[APP]] transgenic mice with moderate Aβ pathology. Our results demonstrate that [[BACE1]] inhibition not only reduces Aβ generation but also downstream AD pathophysiology. The tight correlation between Aβ aggregation in brain and CSF tau levels renders CSF tau a valuable marker to predict the effectiveness of [[BACE1]] inhibitors in current clinical trials.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Animals
* Aspartic Acid Endopeptidases
* Disease Models, Animal
* Enzyme Inhibitors
* Female
* Humans
* Immunoassay
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Picolinic Acids
* Plaque, Amyloid
* Prosencephalon
* Thiazines
* tau Proteins
|keywords=* Alzheimer's disease
* BACE1 inhibitor
* Biomarker
* CSF
* Tau
* Treatment
|full-text-url=https://sci-hub.do/10.1016/j.jalz.2016.09.005
}}
{{medline-entry
|title=Aging process alters hippocampal and cortical secretase activities of Wistar rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27702637
|abstract=A growing body of evidence has demonstrated amyloid plaques in aged brain; however, little attention has been given to amyloid precursor protein ([[APP]]) processing machinery during the healthy aging process. The amyloidogenic and non-amyloidogenic pathways, represented respectively by β- and α-secretases (BACE and TACE), are responsible for [[APP]] cleavage. Our working hypothesis is that the normal aging process could imbalance amyloidogenic and non-amyloidogenic pathways specifically BACE and TACE activities. Besides, although it has been showed that exercise can modulate secretase activities in Alzheimer Disease models the relationship between exercise effects and [[APP]] processing during healthy aging process is rarely studied. Our aim was to investigate the aging process and the exercise effects on cortical and hippocampal BACE and TACE activities and aversive memory performance. Young adult and aged Wistar rats were subjected to an exercise protocol (20min/day for 2 weeks) and to inhibitory avoidance task. Biochemical parameters were evaluated 1h and 18h after the last exercise session in order to verify transitory and delayed exercise effects. Aged rats exhibited impaired aversive memory and diminished cortical TACE activity. Moreover, an imbalance between TACE and BACE activities in favor of BACE activity was observed in aged brain. Moderate treadmill exercise was unable to alter secretase activities in any brain areas or time points evaluated. Our results suggest that aging-related aversive memory decline is partly linked to decreased cortical TACE activity. Additionally, an imbalance between secretase activities can be related to the higher vulnerability to neurodegenerative diseases induced by aging.
|mesh-terms=* ADAM17 Protein
* Age Factors
* Aging
* Amyloid Precursor Protein Secretases
* Animals
* Aspartic Acid Endopeptidases
* Avoidance Learning
* Cerebral Cortex
* Exercise Test
* Gene Expression Regulation, Enzymologic
* Hippocampus
* Male
* Physical Conditioning, Animal
* Rats
* Rats, Wistar
* Time Factors
|keywords=* Aging
* Amyloid precursor protein
* BACE
* Hippocampus
* Prefrontal cortex
* TACE
|full-text-url=https://sci-hub.do/10.1016/j.bbr.2016.09.066
}}
{{medline-entry
|title=Alzheimer-related protein APL-1 modulates lifespan through heterochronic gene regulation in Caenorhabditis elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27557896
|abstract=Alzheimer's disease (AD) is an age-associated disease. Mutations in the amyloid precursor protein ([[APP]]) may be causative or protective of AD. The presence of two functionally redundant [[APP]]-like genes (APLP1/2) has made it difficult to unravel the biological function of [[APP]] during aging. The nematode Caenorhabditis elegans contains a single [[APP]] family member, apl-1. Here, we assessed the function of APL-1 on C. elegans' lifespan and found tissue-specific effects on lifespan by overexpression of APL-1. Overexpression of APL-1 in neurons causes lifespan reduction, whereas overexpression of APL-1 in the hypodermis causes lifespan extension by repressing the function of the heterochronic transcription factor LIN-14 to preserve youthfulness. APL-1 lifespan extension also requires signaling through the FOXO transcription factor DAF-16, heat-shock factor HSF-1, and vitamin D-like nuclear hormone receptor DAF-12. We propose that reinforcing APL-1 expression in the hypodermis preserves the regulation of heterochronic lin-14 gene network to improve maintenance of somatic tissues via DAF-16/FOXO and HSF-1 to promote healthy aging. Our work reveals a mechanistic link of how a conserved [[APP]]-related protein modulates aging.

|keywords=* 
APP

* APL-1
* Alzheimer's disease
* FOXO transcription factor DAF-16
* heat-shock factor HSF-1
* heterochronic gene LIN-14
* lifespan
* vitamin D-like nuclear hormone receptor DAF-12
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5114704
}}
{{medline-entry
|title=Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27559690
|abstract=In 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6'-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5-1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42 as an in vitro model of memory disturbance in Alzheimer's disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor [[APP]] in the brain, which are involved in developing neurodegenerative processes in Alzheimer's disease.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Antioxidants
* Disease Models, Animal
* Humans
* Mitochondria
* Neuroprotective Agents

|full-text-url=https://sci-hub.do/10.1515/revneuro-2016-0036
}}
{{medline-entry
|title=Relation of size of seminal vesicles on ultrasound to premature ejaculation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27538475
|abstract=Myriad biological factors have been proposed to explain premature ejaculation (PE). However, data correlating PE with seminal vesicles (SVs) are sparse. The study aimed to evaluate the relationship between the size of SV and PE. The cross-sectional study included 44 outpatients with PE and 44 volunteers without PE, and the size of SV was compared. Self-estimated intravaginal ejaculatory latency time, the Premature Ejaculation Diagnostic Tool (PEDT), the International Index of Erectile Function-15, and the National Institutes of Health-Chronic Prostatitis Symptom Index were used for assessment of symptoms. Compared to the control group, the PE group had significantly higher mean anterior-posterior diameter (APD) of SV (P < 0.001). The optimal mean APD of SV cutoff level was 9.25 mm for PE. In the PE group, PEDT was also higher with a mean APD of SV ≥9.25 mm compared with mean APD of SV <9.25 mm. PEDT was significantly correlated with the mean APD of SV (r = 0.326, P = 0.031). The seminal plasma proteins were compared between six PE and six matched control cases by mass spectrometry and it was shown that 102 proteins were at least 1.5-fold up- or down-regulated. Among them, [[GGT1]], [[LAMC1]], and [[APP]] were significantly higher in the PE group. These results indicated that men with a larger mean APD of SV might have a higher PEDT score. Transrectal ultrasound of SV should be considered in the evaluation of patients with premature ejaculation. SV might be a potential target for the treatment of patients with PE and ultrasound change in SV.
|mesh-terms=* Adult
* Aged
* Aging
* Case-Control Studies
* Cross-Sectional Studies
* Gonadal Steroid Hormones
* Humans
* Lipids
* Male
* Middle Aged
* Premature Ejaculation
* Reference Values
* Seminal Plasma Proteins
* Seminal Vesicles
* Socioeconomic Factors
* Ultrasonography
* Ultrasonography, Doppler, Color
* Ultrasound, High-Intensity Focused, Transrectal
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566849
}}
{{medline-entry
|title=Restoring Soluble Amyloid Precursor Protein α Functions as a Potential Treatment for Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27531392
|abstract=Soluble amyloid precursor protein α (s[[APP]]α), a secreted proteolytic fragment of nonamyloidogenic amyloid precursor protein ([[APP]]) processing, is known for numerous neuroprotective functions. These functions include but are not limited to proliferation, neuroprotection, synaptic plasticity, memory formation, neurogenesis, and neuritogenesis in cell culture and animal models. In addition, s[[APP]]α influences amyloid-β (Aβ) production by direct modulation of [[APP]] β-secretase proteolysis as well as Aβ-related or unrelated tau pathology, hallmark pathologies of Alzheimer's disease (AD). Thus, the restoration of s[[APP]]α levels and functions in the brain by increasing nonamyloidogenic [[APP]] processing and/or manipulation of its signaling could reduce AD pathology and cognitive impairment. It is likely that identification and characterization of s[[APP]]α receptors in the brain, downstream effectors, and signaling pathways will pave the way for an attractive therapeutic target for AD prevention or intervention. © 2016 Wiley Periodicals, Inc.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Disease Models, Animal
* Humans
|keywords=* APP
* Alzheimer's disease
* Aβ
* Tau
* aging
* biomarker
* cognitive impairment
* memory
* neurogenesis
* neuroprotection
* receptor
* sAPPα
* synaptic plasticity
* therapeutics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296245
}}
{{medline-entry
|title=Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aβ Production and Tau Hyperphosphorylation of the Hippocampus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27518086
|abstract=The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing β-amyloid (Aβ) peptide, a cleaved fragment of amyloid precursor protein ([[APP]]) via β-site amyloid precursor protein-cleaving enzyme 1 ([[BACE1]]) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aβ and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aβ level and phosphorylation of tau. This was accompanied by a significant decrease in the [[BACE1]] level and phosphorylated [[APP]] (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aβ and tau hyperphosphorylation.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Cyclin-Dependent Kinase 5
* Disease Models, Animal
* Down-Regulation
* Drugs, Chinese Herbal
* Hippocampus
* Male
* Mice
* Neurofibrillary Tangles
* Phosphorylation
* tau Proteins
|keywords=* Alzheimer’s disease
* BACE1
* Cyclin-dependent kinase 5 (CDK5)
* Fuzhisan (FZS)
* Tau
* β-Amyloid (Aβ)
|full-text-url=https://sci-hub.do/10.1007/s11064-016-2028-4
}}
{{medline-entry
|title=Hydroxytyrosol mildly improve cognitive function independent of [[APP]] processing in [[APP]]/PS1 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27287957
|abstract=Olive products, the hallmark of Mediterranean diet, are associated with reduced risk of mild cognitive impairment and Alzheimer's disease (AD). We and other groups have shown that hydroxytyrosol (HT), a bioactive compound of olive products, ameliorates oxidative stress, mitochondrial dysfunction, and neural toxicity. However, whether HT in Mediterranean diet acts as a functional ingredient in delaying AD pathogenesis remains unclear. In the present study, [[APP]]/PS1 mice, an animal model of AD, were administrated for 6 months with 5 mg/kg/day of HT, a comparable level of HT in daily Mediterranean diet. HT improved electroencephalography activity and marginally benefited cognitive behavior of transgenic mice. In addition, HT treatment ameliorated mitochondrial dysfunction, reduced mitochondrial carbonyl protein, enhanced superoxide dismutase 2 expression, reversed the phase 2 enzyme system and reduced the levels of brain inflammatory markers, but had no effect on brain β-amyloid (Aβ) accumulation in [[APP]]/PS1 mice. These results suggest that HT may represent as a functional ingredient in Mediterranean diet in ameliorating AD-involved neuronal impairment via modulating mitochondrial oxidative stress, neuronal inflammation, and apoptosis without affecting [[APP]] processing.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Brain
* Cognition
* Diet, Mediterranean
* Disease Models, Animal
* Mice
* Mice, Transgenic
* Mitochondria
* Olea
* Oxidative Stress
* Phenylethyl Alcohol
|keywords=* Alzheimer's disease
* Cognitive function
* Hydroxytyrosol
* Inflammation
* Mediterranean diet
* Oxidative stress
|full-text-url=https://sci-hub.do/10.1002/mnfr.201600332
}}
{{medline-entry
|title=Sideritis spp. Extracts Enhance Memory and Learning in Alzheimer's β-Amyloidosis Mouse Models and Aged C57Bl/6 Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27258424
|abstract=Nowadays, Alzheimer's disease is the most prevalent epiphenomenon of the aging population. Although soluble amyloid-β (Aβ) species (monomers, oligomers) are recognized triggers of the disease, no therapeutic approach is able to stop it. Herbal medicines are used to treat different diseases in many regions of the world. On the Balkan Peninsula, at the eastern Mediterranean Sea, and adjacent regions, Sideritis species are used as traditional medicine to prevent age-related problems in elderly. To evaluate this traditional knowledge in controlled experiments, we tested extracts of two commonly used Sideritis species, Sideritis euboea and Sideritis scardica, with regard to their effects on cognition in [[APP]]-transgenic and aged, non-transgenic C57Bl/6 mice. Additionally, histomorphological and biochemical changes associated with Aβ deposition and treatment were assessed. We found that daily oral treatment with Sideritis spp. extracts highly enhanced cognition in aged, non-transgenic as well as in [[APP]]-transgenic mice, an effect that was even more pronounced when extracts of both species were applied in combination. The treatment strongly reduced Aβ42 load in [[APP]]-transgenic mice, accompanied by increased phagocytic activity of microglia, and increased expression of the α-secretase [[ADAM10]]. Moreover, the treatment was able to fully rescue neuronal loss of [[APP]]-transgenic mice to normal levels as seen in non-transgenic controls. Having the traditional knowledge in mind, our results imply that treatment with Sideritis spp. extracts might be a potent, well-tolerated option for treating symptoms of cognitive impairment in elderly and with regard to Alzheimer's disease by affecting its most prominent hallmarks: Aβ pathology and cognitive decline.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Amyloidosis
* Animals
* Calcium-Binding Proteins
* DNA-Binding Proteins
* Disease Models, Animal
* Humans
* Learning Disabilities
* Maze Learning
* Memory Disorders
* Mice
* Mice, Transgenic
* Microfilament Proteins
* Mutation
* Peptide Fragments
* Phagocytes
* Phosphopyruvate Hydratase
* Plant Extracts
* Presenilin-1
* Sideritis
|keywords=* Aging
* Alzheimer’s disease
* Sideritis spp
* amyloid-β
* microglia
* neuroprotection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981905
}}
{{medline-entry
|title=Amyloid Precursor-Like Protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27267879
|abstract=Amyloid precursor protein knockout mice ([[APP]]-KO) have impaired differentiation of amacrine and horizontal cells. [[APP]] is part of a gene family and its paralogue amyloid precursor-like protein 2 ([[APLP2]]) has both shared as well as distinct expression patterns to [[APP]], including in the retina. Given the impact of [[APP]] in the retina we investigated how [[APLP2]] expression affected the retina using [[APLP2]] knockout mice ([[APLP2]]-KO). Using histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that [[APLP2]]-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults. Moreover, [[APLP2]]-KO displayed a significant decease in ON-bipolar, rod bipolar and type 2 OFF-cone bipolar cells (36, 21 and 63 %, respectively). Reduction of the number of bipolar cells was accompanied with disrupted dendrites, reduced expression of metabotropic glutamate receptor 6 at the dendritic tips and alteration of axon terminals in the OFF laminae of the inner plexiform layer. In contrast, the [[APP]]-KO photoreceptor ribbon synapses and bipolar cells were intact. The [[APLP2]]-KO retina displayed numerous phenotypic similarities with the congenital stationary night blindness, a non-progressive retinal degeneration disease characterized by the loss of night vision. The pathological phenotypes in the [[APLP2]]-KO mouse correlated to altered transcription of genes involved in pre- and postsynatic structure/function, including [[CACNA1F]], [[GRM6]], TRMP1 and Gα0, and a normal scotopic a-wave electroretinogram amplitude, markedly reduced scotopic electroretinogram b-wave and modestly reduced photopic cone response. This confirmed the impaired function of the photoreceptor ribbon synapses and retinal bipolar cells, as is also observed in congenital stationary night blindness. Since congenital stationary night blindness present at birth, we extended our analysis to retinal differentiation and showed impaired differentiation of different bipolar cell subtypes and an altered temporal sequence of development from OFF to ON laminae in the inner plexiform layer. This was associated with the altered expression patterns of bipolar cell generation and differentiation factors, including MATH3, CHX10, [[VSX1]] and [[OTX2]]. These findings demonstrate that [[APLP2]] couples retina development and synaptic genes and present the first evidence that [[APLP2]] expression may be linked to synaptic disease.
|mesh-terms=* Aging
* Amacrine Cells
* Amyloid beta-Protein Precursor
* Animals
* Animals, Newborn
* Cell Differentiation
* Complement System Proteins
* Dendrites
* Eye Diseases, Hereditary
* Gene Deletion
* Genetic Diseases, X-Linked
* Mice, Inbred C57BL
* Mice, Knockout
* Myopia
* Neurogenesis
* Night Blindness
* Photoreceptor Cells, Vertebrate
* Presynaptic Terminals
* RNA, Messenger
* Retinal Bipolar Cells
* Synaptic Transmission
* Transcription Factors
* Transcription, Genetic
|keywords=* Amyloid precursor protein
* Amyloid precursor-like protein 2
* Congenital stationary night blindness
* Differentiation
* Synapses
* Synaptopathy
* Transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4897877
}}
{{medline-entry
|title=Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27207465
|abstract=Alzheimer's disease (AD) is the most common form of neurodegenerative disorder that leads to a decline in cognitive function. In AD, aggregates of amyloid β peptide precede the accumulation of neurofibrillary tangles, both of which are hallmarks of the disease. The great majority (>90 %) of the AD cases are not originated from genetic defects, therefore supporting the central roles of epigenetic modifications that are acquired progressively during the life span. Strong evidences have indicated the implication of epigenetic modifications, including histone modification and DNA methylation, in AD. Recent studies revealed that 5-hydroxymethylcytosine (5hmC) is dynamically regulated during neurodevelopment and aging. We show that amyloid peptide 1-42 (Aβ1-42) could significantly reduce the overall level of 5hmC in vitro. We found that the level of 5hmC displayed differential response to the pathogenesis in different brain regions, including the cortex, cerebellum, and hippocampus of [[APP]]-[[PSEN1]] double transgenic (DTg) mice. We observed a significant decrease of overall 5hmC in hippocampus, but not in cortex and cerebellum, as the DTg mice aged. Genome-wide profiling identified differential hydroxymethylation regions (DhMRs) in DTg mice, which are highly enriched in introns, exons and intergenic regions. Gene ontology analyses indicated that DhMR-associated genes are highly enriched in multiple signaling pathways involving neuronal development/differentiation and neuronal function/survival. 5hmC-mediated epigenetic regulation could potentially be involved in the pathogenesis of AD.
|mesh-terms=* 5-Methylcytosine
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Cell Line
* DNA Methylation
* Disease Models, Animal
* Epigenesis, Genetic
* Genome-Wide Association Study
* Humans
* Mice
* Mice, Transgenic
|keywords=* 5-hydroxymethylcytosine
* Alzheimer’s disease
* Amyloid peptide
* DNA demethylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875608
}}
{{medline-entry
|title=Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency: Concomitant Disruption of Retrograde Trafficking Is Required for Alteration in β-Amyloid Precursor Protein Metabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27179390
|abstract=It is widely accepted that β-amyloid (Aβ) protein plays a pivotal role in Alzheimer disease pathogenesis, and accumulating evidence suggests that endocytic dysfunction is involved in Aβ pathology. Retromer, a conserved multisubunit complex, mediates the retrograde transport of numerous kinds of cargo from endosomes to the trans-Golgi network. Several studies have found that retromer deficiency enhances Aβ pathology both in vitro and in vivo. Cytoplasmic dynein, a microtubule-based motor protein, mediates minus-end-directed vesicle transport via interactions with dynactin, another microtubule-associated protein that also interacts with retromer. Aging attenuates the dynein-dynactin interaction, and dynein dysfunction reproduces age-dependent endocytic disturbance, resulting in the intracellular accumulation of beta-amyloid precursor protein ([[APP]]) and its β-cleavage products, including Aβ. Here, we report that aging itself affects retromer trafficking in cynomolgus monkey brains. In addition, dynein dysfunction reproduces this type of age-dependent retromer deficiency (ie, the endosomal accumulation of retromer-related proteins and [[APP]]. Moreover, we found that knockdown of Rab7, Rab9, or Rab11 did not alter endogenous [[APP]] metabolism, such as that observed in aged monkey brains and in dynein-depleted cells. These findings suggest that dynein dysfunction can cause retromer deficiency and that concomitant disruption of retrograde trafficking may be the key factor underlying age-dependent Aβ pathology.
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Animals
* Dyneins
* Enzyme-Linked Immunosorbent Assay
* Female
* Immunohistochemistry
* Macaca fascicularis
* Male
* Multiprotein Complexes
* Protein Transport
* RNA Interference

|full-text-url=https://sci-hub.do/10.1016/j.ajpath.2016.03.006
}}
{{medline-entry
|title=Possible role of metal ionophore against zinc induced cognitive dysfunction in D-galactose senescent mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26923568
|abstract=Metal ionophores are considered as potential anti-dementia agents, and some are currently undergoing clinical trials. Many metals are known to accumulate and distribute abnormally in the aging brain. Alterations in zinc metal homeostasis in the glutaminergic synapse could contribute to ageing and the pathophysiology of Alzheimer's disease (AD). The present study was designed to investigate the effect of metal ionophores on long term administration of zinc in D-galactose induced senescent mice. The ageing model was established by combined administration of zinc and D-galactose to mice for 6 weeks. A novel metal ionophore, PBT-2 was given daily to zinc-induced d-galactose senescent mice. The cognitive behaviour of mice was monitored using the Morris Water Maze. The anti-oxidant status and amyloidogenic activity in the ageing mouse was measured by determining mito-oxidative parameters and deposition of amyloid β (Aβ) in the brain. Systemic administration of both zinc and D-galactose significantly produced memory deficits, mito-oxidative damage, heightened acetylcholinesterase enzymatic activity and deposition of amyloid-β. Treatment with PBT-2 significantly improved behavioural deficits, biochemical profiles, cellular damage, and curbed the deposition of [[APP]] in zinc-induced senescent mice. These findings suggest that PBT-2, acting as a metal protein attenuating compound, may be helpful in the prevention of AD or alleviation of ageing.
|mesh-terms=* Administration, Oral
* Aging
* Amyloid beta-Peptides
* Animals
* Clioquinol
* Cognition Disorders
* Dose-Response Relationship, Drug
* Galactose
* Injections, Subcutaneous
* Male
* Mice
* Mice, Inbred Strains
* Zinc Sulfate
|keywords=* Ageing
* Metal ionophore
* Mitochondrial dysfunction
* Oxidative stress
* Zinc
|full-text-url=https://sci-hub.do/10.1007/s10534-016-9922-8
}}
{{medline-entry
|title=Partial [[BACE1]] reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of [[APP]]-CTF.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26923405
|abstract=β-amyloid precursor protein ([[APP]]) and amyloid beta peptide (Aβ) are strongly implicated in Alzheimer's disease (AD) pathogenesis, although recent evidence has linked [[APP]]-βCTF generated by [[BACE1]] (β-[[APP]] cleaving enzyme 1) to the development of endocytic abnormalities and cholinergic neurodegeneration in early AD. We show that partial [[BACE1]] genetic reduction prevents these AD-related pathological features in the Ts2 mouse model of Down syndrome. Partially reducing [[BACE1]] by deleting one [[BACE1]] allele blocked development of age-related endosome enlargement in the medial septal nucleus, cerebral cortex, and hippocampus and loss of choline acetyltransferase (ChAT)-positive medial septal nucleus neurons. [[BACE1]] reduction normalized [[APP]]-βCTF elevation but did not alter Aβ40 and Aβ42 peptide levels in brain, supporting a critical role in vivo for [[APP]]-βCTF in the development of these abnormalities. Although ameliorative effects of [[BACE1]] inhibition on β-amyloidosis and synaptic proteins levels have been previously noted in AD mouse models, our results highlight the additional potential value of [[BACE1]] modulation in therapeutic targeting of endocytic dysfunction and cholinergic neurodegeneration in Down syndrome and AD. 
|mesh-terms=* Aging
* Alleles
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Choline O-Acetyltransferase
* Cholinergic Neurons
* Disease Models, Animal
* Down Syndrome
* Endosomes
* Gene Deletion
* Genetic Association Studies
* Mice, Inbred C3H
* Mice, Inbred C57BL
* Mice, Transgenic
* Nerve Degeneration
* Septal Nuclei
|keywords=* APP-βCTF
* Alzheimer's disease
* BACE1
* Basal forebrain cholinergic neurons
* Endosomes
* Trisomic mice
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773919
}}
{{medline-entry
|title=Alzheimer's disease-like [[APP]] processing in wild-type mice identifies synaptic defects as initial steps of disease progression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26759118
|abstract=Alzheimer's disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein ([[APP]]) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid [[APP]] processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant [[APP]] and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human [[APP]], without significant overexpression and to specifically induce its amyloid processing. The human [[APP]], βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both [[PSD]]-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of [[CA1]] hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks. Altogether, this demonstrates that an AD-like [[APP]] processing, yielding to levels of [[APP]], βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Disease Models, Animal
* Disease Progression
* Female
* Hippocampus
* Humans
* Long-Term Potentiation
* Male
* Mice, Inbred C57BL
* Plaque, Amyloid
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709894
}}
{{medline-entry
|title=Overexpression of Swedish mutant [[APP]] in aged astrocytes attenuates excitatory synaptic transmission.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26733247
|abstract=Amyloid precursor protein ([[APP]]), a type I transmembrane protein, has different aspects, namely, performs essential physiological functions and produces β-amyloid peptide (Aβ). Overexpression of neuronal [[APP]] is responsible for synaptic dysfunction. In the central nervous system, astrocytes - a major glial cell type - have an important role in the regulation of synaptic transmission. Although [[APP]] is expressed in astrocytes, it remains unclear whether astrocytic overexpression of mutant [[APP]] affects synaptic transmission. In this study, the effect of astrocytic overexpression of a mutant [[APP]] on the excitatory synaptic transmission was investigated using coculture system of the transgenic (Tg) cortical astrocytes that express the human [[APP]]695 polypeptide with the double mutation K670N   M671L found in a large Swedish family with early onset Alzheimer's disease, and wild-type hippocampal neuron. Significant secretion of Aβ 1-40 and 1-42 was observed in cultured cortical astrocytes from the Tg2576 transgenic mouse that genetically overexpresses Swedish mutant [[APP]]. Under the condition, Tg astrocytes did not affect excitatory synaptic transmission of cocultured wild-type neurons. However, aged Tg astrocytes cultured for 9 weeks elicited a significant decrease in excitatory synaptic transmission in cocultured neurons. Moreover, a reduction in the number of readily releasable synaptic vesicles accompanied a decrease in the number of excitatory synapses in neurons cocultured with aged Tg astrocytes. These observations indicate that astrocytic expression of the mutant [[APP]] is involved in the downregulation of synaptic transmission with age. 
|mesh-terms=* Amyloid beta-Protein Precursor
* Animals
* Animals, Newborn
* Astrocytes
* Cells, Cultured
* Cellular Senescence
* Excitatory Postsynaptic Potentials
* Gene Expression Regulation
* Humans
* Mice
* Mice, Inbred ICR
* Mice, Transgenic
* Mutation
* Sweden
* Synaptic Transmission
|keywords=* Aging
* alzheimer's disease
* amyloid
* astrocyte
* synaptic release
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760399
}}
{{medline-entry
|title=Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26549211
|abstract=The age-dependent deposition of amyloid-β peptides, derived from amyloid precursor protein ([[APP]]), is a neuropathological hallmark of Alzheimer's disease (AD). Despite age being the greatest risk factor for AD, the molecular mechanisms linking ageing to [[APP]] processing are unknown. Here we show that asparagine endopeptidase (AEP), a pH-controlled cysteine proteinase, is activated during ageing and mediates [[APP]] proteolytic processing. AEP cleaves [[APP]] at N373 and N585 residues, selectively influencing the amyloidogenic fragmentation of [[APP]]. AEP is activated in normal mice in an age-dependent manner, and is strongly activated in 5XFAD transgenic mouse model and human AD brains. Deletion of AEP from 5XFAD or [[APP]]/PS1 mice decreases senile plaque formation, ameliorates synapse loss, elevates long-term potentiation and protects memory. Blockade of [[APP]] cleavage by AEP in mice alleviates pathological and behavioural deficits. Thus, AEP acts as a δ-secretase, contributing to the age-dependent pathogenic mechanisms in AD. 
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Blotting, Western
* Brain
* Cysteine Endopeptidases
* Electrical Synapses
* Enzyme-Linked Immunosorbent Assay
* Female
* Fluorescent Antibody Technique
* HEK293 Cells
* Hippocampus
* Humans
* Immunohistochemistry
* Immunoprecipitation
* Long-Term Potentiation
* Male
* Mass Spectrometry
* Memory
* Mice
* Mice, Knockout
* Mice, Transgenic
* Microscopy, Electron
* Middle Aged
* Plaque, Amyloid

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659940
}}
{{medline-entry
|title=Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26530776
|abstract=The human β-amyloid (Aβ) cleaving enzyme (BACE-1) is a target for Alzheimer's disease (AD) treatments. This study was conducted to determine if acacetin extracted from the whole Agastache rugosa plant had anti-BACE-1 and behavioral activities in Drosophila melanogaster AD models and to determine acacetin's mechanism of action. Acacetin (100, 300, and 500 μM) rescued amyloid precursor protein ([[APP]])/BACE1-expressing flies and kept them from developing both eye morphology (dark deposits, ommatidial collapse and fusion, and the absence of ommatidial bristles) and behavioral (motor abnormalities) defects. The reverse transcription polymerase chain reaction analysis revealed that acacetin reduced both the human [[APP]] and BACE-1 mRNA levels in the transgenic flies, suggesting that it plays an important role in the transcriptional regulation of human BACE-1 and [[APP]]. Western blot analysis revealed that acacetin reduced Aβ production by interfering with BACE-1 activity and [[APP]] synthesis, resulting in a decrease in the levels of the [[APP]] carboxy-terminal fragments and the [[APP]] intracellular domain. Therefore, the protective effect of acacetin on Aβ production is mediated by transcriptional regulation of BACE-1 and [[APP]], resulting in decreased [[APP]] protein expression and BACE-1 activity. Acacetin also inhibited [[APP]] synthesis, resulting in a decrease in the number of amyloid plaques. 
|mesh-terms=* Agastache
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Animals, Genetically Modified
* Behavior, Animal
* Disease Models, Animal
* Drosophila
* Eating
* Eye
* Flavones
* Fluorescence Resonance Energy Transfer
* Gene Expression Regulation
* Humans
* Longevity
* Male
* Oleanolic Acid
* Phenotype
* Triterpenes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632086
}}
{{medline-entry
|title=Caspase-dependent degradation of MDMx/MDM4 cell cycle regulatory protein in amyloid β-induced neuronal damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26477779
|abstract=MDMx/MDM4 is a negative regulator of the p53 tumor suppressor protein and is necessary for survival in dividing cells. MDMx is also expressed in postmitotic neurons, with prosurvival roles that are independent of its extensively described roles in carcinogenesis. We and others have shown a role for MDMx loss in neuronal death in vitro and in vivo in several neurodegenerative diseases. Further, we have recently shown that MDMx is targeted for proteolytic degradation by calcium-dependent proteases, calpains, in neurons in vitro, and that MDMx overexpression provided partial neuroprotection in a model of HIV-associated neurodegeneration. Here, we assessed whether amyloid β (Aβ)-induced MDMx degradation occurred in Alzheimer's Disease (AD) models. Our data shows an age-dependent reduction in MDMx levels in cholinergic neurons within the cortex of adult mice expressing the swedish mutant of the amyloid precursor protein, [[APP]] in the Tg2576 murine model of AD. In vitro, Aβ treatment of primary cortical neurons led to the caspase-dependent MDMx degradation. Our findings suggest that MDMx degradation associated with neuronal death occurs via caspase activation in neurons, and that the progressive loss of MDMx protein represents a potential mechanism of Aβ-induced neuronal death during disease progression in AD. 
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Caspases
* Cells, Cultured
* Female
* Mice
* Mice, Mutant Strains
* Nerve Degeneration
* Neurons
* Peptide Fragments
* Proto-Oncogene Proteins
* Proto-Oncogene Proteins c-mdm2
* Ubiquitin-Protein Ligases
|keywords=* Alzheimer’s disease
* Amyloid β
* Caspase
* MDM4l
* MDMx
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679561
}}
{{medline-entry
|title=Multiple mechanisms of age-dependent accumulation of amyloid beta protein in rat brain: Prevention by dietary supplementation with N-acetylcysteine, α-lipoic acid and α-tocopherol.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26463138
|abstract=The aged brain may be used as a tool to investigate altered metabolism of amyloid beta protein (Aβ42) that may have implications in the pathogenesis of Alzheimer's disease (AD). In the present study, we have observed a striking increase in the amyloid precursor protein ([[APP]]) level in the brain cortex of aged rats (22-24 months) along with a mild but statistically significant increase in the level of [[APP]] mRNA. Moreover, the activity of β secretase is elevated (nearly 55%) and that of neprilysin diminished (48%) in brain cortex of aged rats compared to that in young rats (4-6 months). All these changes lead to a markedly increased accumulation of Aβ42 in brain cortical tissue of aged rats. Long-term dietary supplementation of rats with a combination of N-acetylcysteine, α-lipoic and α-tocopherol from 18 months onwards daily till the sacrifice of the animals by 22-24 months, attenuates the age-related alterations in amyloid beta metabolism. In separate experiments, a significant impairment of spatial learning and memory has been observed in aged rats, and the phenomenon is remarkably prevented by the dietary supplementation of the aged animals by the same combination of N-acetylcysteine, α-lipoic acid and α-tocopherol. The results call for further explorations of this combination in suitable animal models in ameliorating AD related brain deficits.
|mesh-terms=* Acetylcysteine
* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Dietary Supplements
* Drug Therapy, Combination
* Maze Learning
* Peptide Fragments
* Rats
* Rats, Wistar
* Thioctic Acid
* alpha-Tocopherol
|keywords=* Alzheimer's disease
* Amyloid beta protein
* Amyloid precursor protein
* Antioxidant
* Neprilysin
* β Secretase
|full-text-url=https://sci-hub.do/10.1016/j.neuint.2015.10.003
}}
{{medline-entry
|title=Chronic alpha-linolenic acid treatment alleviates age-associated neuropathology: Roles of PERK/eIF2α signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26399745
|abstract=Aging is a principal risk factor for neurodegenerative diseases and especially shares similar pathologic mechanisms to Alzheimer's disease (AD). Amyloid-β (Aβ) plaques deposition and neurofibrillary tangles (NFTs) are the prominent age-dependent pathologies implicated in the cognitive deficits. Accumulation of mis-folded proteins in the endoplasmic reticulum triggers a cellular stress response called the unfolded protein response (UPR), the activation of which is increased in AD patients. However, the UPR relates to the pathological hallmarks of aging is still elusive. In this study, we report that long-term supplement of α-linolenic acid (ALA), starting before the onset of disease symptoms (6month-old), prevents the age-related memory deficits during natural aging. The amelioration of the memory impairment is associated with a decrease in UPR related markers [glucose regulated protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic Initiation Factor 2α (eIF2α)]. ALA suppressed the PERK/eIF2α signaling, which may be responsible for multifaceted memory-deteriorating and neurodegenerative mechanisms, including inhibition of Aβ production by suppressing β-site [[APP]]-cleaving enzyme 1 (BACE1) expression, enhancement of cAMP response element binding protein (CREB) function via down-regulating activating transcription factor 4 (ATF4), and suppression of Tau phosphorylation by inhibiting glycogen synthase kinase 3β (GSK-3β) pathway. Taken together, our findings provide new insights into the link between ALA and PERK/eIF2α signaling, which could contribute to a better understanding of an ALA-mediated protective effect in aging-associated neuropathology. 
|mesh-terms=* Aging
* Animals
* Disease Models, Animal
* Female
* Memory Disorders
* Rats
* Rats, Sprague-Dawley
* Signal Transduction
* alpha-Linolenic Acid
* eIF-2 Kinase
|keywords=* Aging
* Endoplasmic reticulum stress
* Learning and memory
* Unfold protein response
* α-Linolenic acid
|full-text-url=https://sci-hub.do/10.1016/j.bbi.2015.09.012
}}
{{medline-entry
|title=Differential interaction of Apolipoprotein-E isoforms with insulin receptors modulates brain insulin signaling in mutant human amyloid precursor protein transgenic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26346625
|abstract=It is unclear how human apolipoprotein E4 (ApoE4) increases the risk for Alzheimer's disease (AD). Although Aβ levels can lead to insulin signaling impairment, these experiments were done in the absence of human ApoE. To examine ApoE role, we crossed the human ApoE-targeted replacement mice with mutant human amyloid precursor protein ([[APP]]) mice. In 26 week old mice with lower Aβ levels, the expression and phosphorylation of insulin signaling proteins remained comparable among [[APP]], ApoE3x[[APP]] and ApoE4x[[APP]] mouse brains. When the mice aged to 78 weeks, these proteins were markedly reduced in [[APP]] and ApoE4x[[APP]] mouse brains. While Aβ can bind to insulin receptor, how ApoE isoforms modulate this interaction remains unknown. Here, we showed that ApoE3 had greater association with insulin receptor as compared to ApoE4, regardless of Aβ42 concentration. In contrast, ApoE4 bound more Aβ42 with increasing peptide levels. Using primary hippocampal neurons, we showed that ApoE3 and ApoE4 neurons are equally sensitive to physiological levels of insulin. However, in the presence of Aβ42, insulin failed to elicit a downstream response only in ApoE4 hippocampal neurons. Taken together, our data show that ApoE genotypes can modulate this Aβ-mediated insulin signaling impairment. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Apolipoprotein E4
* Apolipoproteins E
* Brain
* Humans
* Insulin
* Insulin Receptor Substrate Proteins
* Mice
* Mice, Transgenic
* Mutation
* Phosphorylation
* Protein Binding
* Protein Isoforms
* Proto-Oncogene Proteins c-akt
* Pyramidal Cells
* Receptor, Insulin
* Signal Transduction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561911
}}
{{medline-entry
|title=Age- and Sex-Associated Effects on Acute-Phase Proteins in Göttingen Minipigs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26310463
|abstract=Göttingen minipigs are a useful model for diseases having an inflammatory component, and the associated use of acute-phase proteins ([[APP]]) as biomarkers of inflammation warrants establishment of their reference ranges. The objective of this study was to establish reference values for selected [[APP]] in Göttingen minipigs and to investigate the effects of age, sex, and various stimuli on these ranges. Serum concentrations of C-reactive protein ([[CRP]]), serum amyloid A (SAA), haptoglobin, pig major acute-phase protein (PMAP), albumin, and porcine α-1 acid glycoprotein (PAGP) were evaluated in 4 age groups (6, 16, 24 and 40-48 wk) of male and female Göttingen minipigs. In addition, minipigs were tested under 2 housing conditions, after acute LPS challenge, and after diet-induced obesity with and without mild diabetes. Changing the pigs to a new environment induced significant increases in [[CRP]], PMAP, haptoglobin and PAGP and a decrease in albumin. An acute LPS stimulus increased [[CRP]], PMAP, haptoglobin, and SAA; PAGP was unchanged and albumin decreased. Obese pigs with and without diabetes showed increases in [[CRP]] and PAGP, albumin decreased, and haptoglobin and SAA were unchanged. PMAP was increased only in obese pigs without diabetes. In conclusion, reference values for [[CRP]], PMAP, haptoglobin, SAA, PAGP and albumin were established for male and female Göttingen minipigs of different ages. These [[APP]] were influenced by age and sex, underlining the importance of considering these factors when designing and interpreting studies including aspects of inflammation. In addition, an [[APP]] response was verified after both acute and chronic stimuli. 
|mesh-terms=* Acute-Phase Proteins
* Age Factors
* Aging
* Animals
* Diabetes Mellitus, Experimental
* Diet, High-Fat
* Female
* Housing, Animal
* Inflammation
* Lipopolysaccharides
* Male
* Obesity
* Reference Values
* Sex Factors
* Streptozocin
* Swine
* Swine, Miniature
* Time Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549679
}}
{{medline-entry
|title=Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26260389
|abstract=The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein ([[APP]]) abolished the phenotype of the [[APP]] AD model. This evidence is complicated by the uncertain impact of overexpressing mutant [[APP]], rather than Aβ alone, and for potential interactions between tau and overexpressed [[APP]]. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking [[APP]] to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased [[APP]] levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets. 
|mesh-terms=* Age Factors
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Enzyme-Linked Immunosorbent Assay
* Exploratory Behavior
* Hippocampus
* In Vitro Techniques
* Iron
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Peptide Fragments
* Phosphopyruvate Hydratase
* Recognition, Psychology
* Time Factors
* tau Proteins
|keywords=* Aging
* Alzheimer’s disease
* Iron
* Neuroprotection
* Tau
* β-Amyloid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604188
}}
{{medline-entry
|title=Nilotinib and bosutinib modulate pre-plaque alterations of blood immune markers and neuro-inflammation in Alzheimer's disease models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26235435
|abstract=Alzheimer's disease (AD) brains exhibit plaques and tangles in association with inflammation. The non-receptor tyrosine kinase Abl is linked to neuro-inflammation in AD. Abl inhibition by nilotinib or bosutinib facilitates amyloid clearance and may decrease inflammation. Transgenic mice that express Dutch, Iowa and Swedish [[APP]] mutations (Tg[[APP]]) and display progressive Aβ plaque deposition were treated with tyrosine kinase inhibitors (TKIs) to determine pre-plaque effects on systemic and CNS inflammation using milliplex® ELISA. Plaque Aβ was detected at 4months in Tg[[APP]] and pre-plaque intracellular Aβ accumulation (2.5months) was associated with changes of cytokines and chemokines prior to detection of glial changes. Plaque formation correlated with increased levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1α, IL-1β) and markers of immunosuppressive and adaptive immunity, including, IL-4, IL-10, IL-2, IL-3, Vascular Endothelial Growth Factor (VEGF) and IFN-γ. An inverse relationship of chemokines was observed as [[CCL2]] and [[CCL5]] were lower than WT mice at 2months and significantly increased after plaque appearance, while soluble [[CX3CL1]] decreased. A change in glial profile was only robustly detected at 6months in Tg-[[APP]] mice and TKIs reduced astrocyte and dendritic cell number with no effects on microglia, suggesting alteration of brain immunity. Nilotinib decreased blood and brain cytokines and chemokines and increased [[CX3CL1]]. Bosutinib increased brain and blood IL-10 and [[CX3CL1]], suggesting a protective role for soluble [[CX3CL1]]. Taken together these data suggest that TKIs regulate systemic and CNS immunity and may be useful treatments in early AD through dual effects on amyloid clearance and immune modulation. 
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Aniline Compounds
* Animals
* Astrocytes
* Brain
* Cytokines
* Disease Models, Animal
* Enzyme Inhibitors
* Female
* Humans
* Intracellular Space
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Microglia
* Neuroimmunomodulation
* Nitriles
* Peptide Fragments
* Plaque, Amyloid
* Protein-Tyrosine Kinases
* Pyrimidines
* Quinolines
|keywords=* CX3CL1
* bosutinib
* inflammation
* nilotinib
* plaque
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2015.07.070
}}
{{medline-entry
|title=The [[APP]] A673T frequency differs between Nordic countries.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26239177
|abstract=A coding gene variant A673T (rs63750847) in the [[APP]] gene has recently been recognized as a protective variant of late-onset Alzheimer's Disease in a large Icelandic population and has been observed recurrently in populations from Nordic countries. The variant also was related to longevity in the Icelandic population. However, because of the extreme rarity of A673T in non-Nordic populations, the association with Alzheimer's disease has not yet been formally replicated. Because the variant has not been reported among the Danes, we aimed to study its frequency among healthy middle-age twins and oldest-old singletons and explore the possible effects on longevity and cognitive abilities. Surprisingly, only 1 of 3487 unrelated Danes carried the A673T variant, (0.014% [95% CI 0.000-0.080]), which was significantly lower than in the other Nordic countries averaging to 0.43% (95% CI 0.40-0.46). In conclusion, the A673T variant is rarer in Danes than other Nordic countries, thus precluding assessment of association with longevity or cognitive functioning.
|mesh-terms=* Aged, 80 and over
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Cognition
* Genetic Association Studies
* Genetic Variation
* Humans
* Longevity
* Middle Aged
* Scandinavian and Nordic Countries
* Twin Studies as Topic
|keywords=* Aging
* Alzheimers
* Amyloid beta
* Cognition
* Dementia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562869
}}
{{medline-entry
|title=GSK3β Interactions with Amyloid Genes: An Autopsy Verification and Extension.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26194614
|abstract=Glyocogen synthase kinase 3 (GSK3) plays an important role in the pathophysiology of Alzheimer's disease (AD) through the phosphorylation of tau. Recent work has suggested that GSK3β also plays a role in the amyloid pathway of AD through genetic interactions with [[APP]] and [[APBB2]] on in vivo measures of amyloid. This project extends the previously identified genotype interactions to an autopsy measure of amyloid, while also testing the same interactions leveraging gene expression data quantified in the prefrontal cortex. 797 participants (251 cognitively normal, 196 mild cognitive impairment, and 350 Alzheimer's disease) were drawn from the Religious Orders Study and Rush Memory and Aging Project. A mean score of amyloid load was calculated across eight brain regions, gene expression levels from frozen sections of the dorsolateral prefrontal cortex were quantified using RNA amplification, and expression signals were generated using Beadstudio. Three SNPs previously identified in genetic interactions were genotyped using the Illumina 1M genotyping chip. Covariates included age, sex, education, and diagnosis. We were able to evaluate 2 of the 3 previously identified interactions, of which the interaction between GSK3β (rs334543) and [[APBB2]] (rs2585590) was found in this autopsy sample (p = 0.04). We observed a comparable interaction between GSK3β and [[APBB2]] when comparing the highest tertile of gene expression to the lowest tertile, t(1) = -2.03, p = 0.043. These results provide additional evidence of a genetic interaction between GSK3β and [[APBB2]] and further suggest that GSK3β is involved in the pathophysiology of both of the primary neuropathologies of Alzheimer's disease.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid
* Brain
* Cognitive Dysfunction
* Cohort Studies
* Educational Status
* Female
* Follow-Up Studies
* Gene Expression
* Glycogen Synthase Kinase 3
* Glycogen Synthase Kinase 3 beta
* Humans
* Male
* Polymorphism, Single Nucleotide
* Sex Characteristics
* United States

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625986
}}
{{medline-entry
|title=The amyloid precursor protein ([[APP]]) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26174856
|abstract=p44 is a short isoform of the tumor suppressor protein p53 that is regulated in an age-dependent manner. When overexpressed in the mouse, it causes a progeroid phenotype that includes premature cognitive decline, synaptic defects, and hyperphosphorylation of tau. The hyperphosphorylation of tau has recently been linked to the ability of p44 to regulate transcription of relevant tau kinases. Here, we report that the amyloid precursor protein ([[APP]]) intracellular domain (AICD), which results from the processing of the [[APP]], regulates translation of p44 through a cap-independent mechanism that requires direct binding to the second internal ribosome entry site (IRES) of the p53 mRNA. We also report that AICD associates with nucleolin, an already known IRES-specific trans-acting factor that binds with p53 IRES elements and regulates translation of p53 isoforms. The potential biological impact of our findings was assessed in a mouse model of Alzheimer's disease. In conclusion, our study reveals a novel aspect of AICD and p53/p44 biology and provides a possible molecular link between [[APP]], p44, and tau. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Cells, Cultured
* Disease Models, Animal
* Humans
* Internal Ribosome Entry Sites
* Mice, Transgenic
* Peptide Fragments
* Phosphorylation
* Protein Binding
* Protein Biosynthesis
* Protein Structure, Tertiary
* RNA, Messenger
* Transcription Factors
* Tumor Suppressor Protein p53
* tau Proteins
|keywords=* AICD
* Aging
* Alzheimer's disease
* IRES
* p44
* p53
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562799
}}
{{medline-entry
|title=[[SNX15]] Regulates Cell Surface Recycling of [[APP]] and Aβ Generation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26115702
|abstract=Amyloid-β (Aβ) peptide plays an essential role in the pathogenesis of Alzheimer's disease (AD) and is generated from amyloid-β precursor protein ([[APP]]) through sequential proteolytic cleavages by β-site [[APP]] cleaving enzyme 1 ([[BACE1]]) and γ-secretase. Trafficking dysregulation of [[APP]], [[BACE1]], and γ-secretase may affect Aβ generation and disease pathogenesis. Sorting nexin 15 ([[SNX15]]) is known to regulate protein trafficking. Here, we report that [[SNX15]] is abundantly expressed in mouse neurons and astrocytes. In addition, we show that although not affecting the protein levels of [[APP]], [[BACE1]], and γ-secretase components and the activity of [[BACE1]] and γ-secretase, overexpression and downregulation of [[SNX15]] reduce and promote Aβ production, respectively. Furthermore, we find that overexpression of [[SNX15]] increases [[APP]] protein levels in cell surface through accelerating [[APP]] recycling, whereas downregulation of [[SNX15]] has an opposite effect. Finally, we show that exogenous expression of human [[SNX15]] in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Aβ pathology in the hippocampus and improve short-term working memory in the [[APP]]swe/PSEN1dE9 double transgenic AD model mice. Together, our results suggest that [[SNX15]] regulates the recycling of [[APP]] to cell surface and, thus, its processing for Aβ generation.
|mesh-terms=* Aging
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Cell Line
* Cell Membrane
* Down-Regulation
* Endocytosis
* Humans
* Memory, Short-Term
* Mice, Inbred C57BL
* Mice, Transgenic
* Protein Processing, Post-Translational
* Sorting Nexins
|keywords=* Alzheimer’s disease
* Amyloid-β
* Amyloid-β precursor protein
* SNX15
* Trafficking
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691577
}}
{{medline-entry
|title=DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25933409
|abstract=Alzheimer's disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein ([[APP]]) or genes involved in the processing of [[APP]] including the presenilins (e.g. [[PSEN1]] or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated [[APP]]swe and [[PSEN1]]de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant [[APP]] but the impact of [[PSEN1]]de9 has not been tested. Our study shows that DBA/2J.[[APP]]swe[[PSEN1]]de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.[[APP]]swe[[PSEN1]]de9 mice-70% of DBA/2J.[[APP]]swe[[PSEN1]]de9 mice die between 2-3 months of age. Of the DBA/2J.[[APP]]swe[[PSEN1]]de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.[[APP]]swe[[PSEN1]]de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement [[C5]] activity. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid
* Amyloid beta-Protein Precursor
* Animals
* Chromosomes, Mammalian
* Complement C5
* Disease Models, Animal
* Disease Progression
* Disease Susceptibility
* Mice, Inbred C57BL
* Mice, Inbred DBA
* Mice, Transgenic
* Microglia
* Mutagenesis, Insertional
* Neurons
* Phenotype
* Plaque, Amyloid
* Presenilins
* Seizures
* Transgenes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416920
}}
{{medline-entry
|title=Manipulations of amyloid precursor protein cleavage disrupt the circadian clock in aging Drosophila.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25766673
|abstract=Alzheimer's disease (AD) is a neurodegenerative disease characterized by severe cognitive deterioration. While causes of AD pathology are debated, a large body of evidence suggests that increased cleavage of Amyloid Precursor Protein ([[APP]]) producing the neurotoxic Amyloid-β (Aβ) peptide plays a fundamental role in AD pathogenesis. One of the detrimental behavioral symptoms commonly associated with AD is the fragmentation of sleep-activity cycles with increased nighttime activity and daytime naps in humans. Sleep-activity cycles, as well as physiological and cellular rhythms, which may be important for neuronal homeostasis, are generated by a molecular system known as the circadian clock. Links between AD and the circadian system are increasingly evident but not well understood. Here we examined whether genetic manipulations of [[APP]]-like ([[APP]]L) protein cleavage in Drosophila melanogaster affect rest-activity rhythms and core circadian clock function in this model organism. We show that the increased β-cleavage of endogenous [[APP]]L by the β-secretase (dBACE) severely disrupts circadian behavior and leads to reduced expression of clock protein PER in central clock neurons of aging flies. Our data suggest that behavioral rhythm disruption is not a product of [[APP]]L-derived Aβ production but rather may be caused by a mechanism common to both α and β-cleavage pathways. Specifically, we show that increased production of the endogenous Drosophila Amyloid Intracellular Domain (dAICD) caused disruption of circadian rest-activity rhythms, while flies overexpressing endogenous [[APP]]L maintained stronger circadian rhythms during aging. In summary, our study offers a novel entry point toward understanding the mechanism of circadian rhythm disruption in Alzheimer's disease. 
|mesh-terms=* Age Factors
* Aging
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Animals, Genetically Modified
* Central Nervous System
* Circadian Clocks
* Disintegrins
* Drosophila Proteins
* Drosophila melanogaster
* Fourier Analysis
* Gene Expression Regulation
* Green Fluorescent Proteins
* Longevity
* Metalloendopeptidases
* Motor Activity
* Neurons
* Period Circadian Proteins
|keywords=* Alzheimer's disease
* Amyloid intracellular domain
* Amyloid precursor protein
* BACE
* Circadian rhythms
* Drosophila
* period gene
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402283
}}
{{medline-entry
|title=Gr33a modulates Drosophila male courtship preference.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25586066
|abstract=In any gamogenetic species, attraction between individuals of the opposite sex promotes reproductive success that guarantees their thriving. Consequently, mate determination between two sexes is effortless for an animal. However, choosing a spouse from numerous attractive partners of the opposite sex needs deliberation. In Drosophila melanogaster, both younger virgin females and older ones are equally liked options to males; nevertheless, when given options, males prefer younger females to older ones. Non-volatile cuticular hydrocarbons, considered as major pheromones in Drosophila, constitute females' sexual attraction that act through males' gustatory receptors (Grs) to elicit male courtship. To date, only a few putative Grs are known to play roles in male courtship. Here we report that loss of Gr33a function or abrogating the activity of Gr33a neurons does not disrupt male-female courtship, but eliminates males' preference for younger mates. Furthermore, ectopic expression of human amyloid precursor protein ([[APP]]) in Gr33a neurons abolishes males' preference behavior. Such function of [[APP]] is mediated by the transcription factor forkhead box O (dFoxO). These results not only provide mechanistic insights into Drosophila male courtship preference, but also establish a novel Drosophila model for Alzheimer's disease (AD). 
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Animals
* Courtship
* Drosophila Proteins
* Drosophila melanogaster
* Female
* Forkhead Transcription Factors
* Hydrocarbons
* Integumentary System
* Male
* Mating Preference, Animal
* Mutation
* Neurons
* Receptors, Cell Surface

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648378
}}
{{medline-entry
|title=Intraventricular human immunoglobulin distributes extensively but fails to modify amyloid in a mouse model of amyloid deposition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25115543
|abstract=Intravenous immunoglobulin infusions into Alzheimer patients have been found to provide cognitive benefit over a period of 6 mo in open label studies. One suggestion has been that these preparations contain small amounts of antibodies directed against monomeric and oligomeric Aβ which underlie their effectiveness in patients. To test this hypothesis, we infused Gammagard, a version of intravenous immunoglobulin (IVIG), into the lateral ventricle of amyloid precursor protein ([[APP]]) transgenic mice with pre-existing amyloid deposits. Mice were infused over 4 weeks, and tested behaviorally for the last 2 weeks of treatment. Brains were analyzed for histopathology. We found widespread distribution of human-immunoglobulin G (h-IgG) staining in the mouse forebrain, including cerebral cortices and hippocampus. Some cortical neurons appeared to concentrate the h-IgG, but we did not detect evidence of amyloid plaque labeling by h-IgG. The IVIG-treated mice had no change in phenotype compared to saline-infused animals with respect to activity, learning and memory, or amyloid deposition. [[APP]] mice infused with an anti-Aβ monoclonal antibody did show some reduction in amyloid deposits. These data do not support the argument that anti-Aβ antibodies in IVIG preparations are responsible for cognitive benefits seen with these preparations.
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Amyloidosis
* Animals
* Brain
* Disease Models, Animal
* Humans
* Immunoglobulin G
* Immunohistochemistry
* Immunologic Factors
* Infusions, Intraventricular
* Maze Learning
* Mice, Inbred C57BL
* Mice, Transgenic
* Motor Activity
* Plaque, Amyloid

|full-text-url=https://sci-hub.do/10.2174/1567205011666140812114341
}}
{{medline-entry
|title=Omega-3 polyunsaturated fatty acids improve mitochondrial dysfunction in brain aging--impact of Bcl-2 and NPD-1 like metabolites.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24972878
|abstract=The present study investigated the effects of orally administered long chain omega-3 polyunsaturated fatty acids (PUFA) on mitochondrial function and processing of the amyloid precursor protein ([[APP]]) in brains of young (3 months old) and aged (24 months old) NMRI-mice. Neuroprotective properties of fish oil (FO) (1.6 ml/kg p.o.) were assessed ex vivo after 21 days in dissociated brain cells (DBC) and isolated mitochondria. Docosahexaenoic acid (DHA) levels were significantly lower in blood and brains of aged mice which were compensated by FO administration. Isolated DBC and mitochondria from aged mice showed significantly lower adenosine triphosphate (ATP) levels and reduced activity of complexes I II and IV of the mitochondrial respiration system, respectively. FO restored the age-related decrease in respiration and improved ATP production. Moreover, FO increased the levels of anti-apoptotic Bcl-2 protein. Cell membrane fractions isolated from the brain of aged mice exhibited lower membrane fluidity, which was partially improved under FO treatment. In comparison to young animals, levels of neuroprotective s[[APP]]α were significantly lower in the brain of aged mice. However, levels of s[[APP]]α, Aβ and C-terminal [[APP]] fragments (CTF) were largely unchanged after FO treatment in aged mice. Neuroprotectin D-1 (NPD-1) represents a neuroprotective compound that is derived from unesterified DHA. Levels of NPD1-like metabolites (NPD1-like) and of unesterified DHA were significantly increased in brains of aged mice. FO treatment further strongly increased NPD1-like levels indicating an accelerated conversion rate of free DHA to NPD1-like. Our findings provide new mechanisms underlying the neuroprotective actions of omega-3 PUFA and identified FO as a promising nutraceutical to delay age-related mitochondrial dysfunction in the brain.
|mesh-terms=* Administration, Oral
* Aging
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Cells, Cultured
* Docosahexaenoic Acids
* Fatty Acids, Omega-3
* Female
* Membrane Fluidity
* Mice
* Mitochondria
* Neuroprotective Agents
* Proto-Oncogene Proteins c-bcl-2
|keywords=* Aging
* Bioenergetics
* Brain
* Docosahexaenoic acid
* Fish oil
* Omega-3 fatty acids
|full-text-url=https://sci-hub.do/10.1016/j.plefa.2014.05.008
}}
{{medline-entry
|title=Enhanced defense against mitochondrial hydrogen peroxide attenuates age-associated cognition decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24906890
|abstract=Increased mitochondrial hydrogen peroxide (H2O2) is associated with Alzheimer's disease and brain aging. Peroxiredoxin 3 (Prdx3) is the key mitochondrial antioxidant defense enzyme in detoxifying H2O2. To investigate the importance of mitochondrial H2O2 in age-associated cognitive decline, we compared cognition between aged (17-19 months) [[APP]] transgenic mice and [[APP]]/Prdx3 double transgenic mice (d[[TG]]) and between old (24 months) wild-type mice and Prdx3 transgenic mice ([[TG]]). Compared with aged [[APP]] mice, aged d[[TG]] mice showed improved cognition that was correlated with reduced brain amyloid beta levels and decreased amyloid beta production. Old [[TG]] mice also showed significantly increased cognitive ability compared with old wild-type mice. Both aged d[[TG]] mice and old [[TG]] mice had reduced mitochondrial oxidative stress and increased mitochondrial function. Moreover, CREB signaling, a signaling pathway important for cognition was enhanced in both aged d[[TG]] mice and old [[TG]] mice. Thus, our results indicate that mitochondrial H2O2 is a key culprit of age-associated cognitive impairment, and that a reduction of mitochondrial H2O2 could improve cognition by maintaining mitochondrial health and enhancing CREB signaling.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Brain
* Cognition
* Cognition Disorders
* Cyclic AMP Response Element-Binding Protein
* Hydrogen Peroxide
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria
* Molecular Targeted Therapy
* Oxidative Stress
* Peroxiredoxin III
* Signal Transduction
|keywords=* Alzheimer's disease
* Beta-amyloid
* Brain aging
* Mitochondria
* Mitochondrial H(2)O(2)
* Oxidative stress
* Peroxiredoxin 3
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2014.05.007
}}
{{medline-entry
|title=Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the [[APP]]/Ld transgenic mouse model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24885175
|abstract=The role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer's disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase γ (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age. We crossed the D257A mice with a well-established transgenic AD mouse model ([[APP]]/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect Aβ synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that Aβ42 levels along with Aβ42 plaque density were increased in D257A; [[APP]]/Ld bigenic mice compared to [[APP]]/Ld monogenic mice. Elevated Aβ production was not responsible for increased amyloid pathology, as levels of [[BACE1]], PS1, C99, and C83 were unchanged in D257A; [[APP]]/Ld compared to [[APP]]/Ld mice. However, the levels of a major Aβ clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the [[APP]] transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; [[APP]]/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; [[APP]]/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei. Overall, our results implicate synergism between the effects of the PolgA D257A mutation and Aβ in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of Aβ.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Atrophy
* Brain
* DNA, Mitochondrial
* Disease Models, Animal
* Enzyme-Linked Immunosorbent Assay
* Fluorescent Antibody Technique
* Gene Knock-In Techniques
* Humans
* Immunoblotting
* Mice
* Mice, Transgenic
* Mutation
* Plaque, Amyloid

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028006
}}
{{medline-entry
|title=Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of β-amyloid by cells other than excitatory neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24599465
|abstract=Rare, familial, early-onset autosomal dominant forms of familial Alzheimer's disease (FAD) are caused by mutations in genes encoding β-amyloid (Aβ) precursor protein ([[APP]]), presenilin-1 (PS1), and presenilin-2. Each of these genes is expressed ubiquitously throughout the CNS, but a widely held view is that excitatory neurons are the primary (or sole) source of the Aβ peptides that promote synaptic dysfunction and neurodegeneration. These efforts notwithstanding, [[APP]] and the enzymes required for Aβ production are synthesized by many additional cell types, and the degree to which those cells contribute to the production of Aβ that drives deposition in the CNS has not been tested. We generated transgenic mice in which expression of an ubiquitously expressed, FAD-linked mutant [[PSEN1]] gene was selectively inactivated within postnatal forebrain excitatory neurons, with continued synthesis in all other cells in the CNS. When combined with an additional transgene encoding an FAD-linked [[APP]] "Swedish" variant that is synthesized broadly within the CNS, cerebral Aβ deposition during aging was found to be unaffected relative to mice with continued mutant PS1 synthesis in excitatory neurons. Thus, Aβ accumulation is non-cell autonomous, with the primary age-dependent contribution to cerebral Aβ deposition arising from mutant PS1-dependent cleavage of [[APP]] within cells other than excitatory neurons. 
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Animals
* Cells, Cultured
* Humans
* Male
* Mice
* Mice, Inbred C3H
* Mice, Inbred C57BL
* Mice, Transgenic
* Neurons
* Plaque, Amyloid
|keywords=* APP
* amyloid deposition
* dementia
* mouse model
* neurodegeneration
* presenilin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942582
}}
{{medline-entry
|title=[[GRK5]] dysfunction accelerates tau hyperphosphorylation in [[APP]] (swe) mice through impaired cholinergic activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24598771
|abstract=Recent studies have suggested that G-protein-coupled receptor kinase 5 ([[GRK5]]) deficiency plays a significant role in the pathogenesis of early Alzheimer's disease. Mild soluble β-amyloid accumulation can result in reduced membrane (functional) and elevated cytosolic levels of [[GRK5]]. Dysfunction of [[GRK5]] impairs the desensitization of presynaptic muscarinic 2 (M2) autoreceptors, which results in presynaptic M2 hyperactivity and inhibits acetylcholine (ACh) release. GRK dysfunction also promotes a deleterious cycle that further increases β-amyloid accumulation and exaggerates tau hyperphosphorylation in the hippocampus. However, the pathogenic effect of [[GRK5]] dysfunction through targeting tau hyperphosphorylation remains unclear. Here we examined not only the reduced membrane (functional) and elevated cytosolic levels of [[GRK5]] but also the increased levels of hyperphosphorylated tau in the hippocampi of aged [[APP]](swe) mice (11 months of age). Moreover, western blotting analyses revealed the changes in the location of activity of both protein kinase C (PKC) and glycogen synthase kinase3β (GSK3β) in the hippocampus of aged [[APP]](swe) mice in which [[GRK5]] translocation occurred. Moreover, treatment with methoctramine, a selective M2 antagonist, partially corrected the difference between wild-type control mice and [[GRK5]]-dysfunctional [[APP]] (swe) mice in hippocampal ACh release, PKC and GSK3β activities, as well as tau hyperphosphorylation. In contrast, the GSK3β inhibitor lithium chloride significantly reduced tau hyperphosphorylation in [[GRK5]]-defective [[APP]] (swe) mice, but failed to enhance PKC activity and ACh release in the hippocampi of [[GRK5]]-defective [[APP]] (swe) mice. Taken together, these findings indicate that [[GRK5]] dysfunction accelerated tau hyperphosphorylation in [[APP]](swe) mice by activating GSK3β through impaired cholinergic activity. 
|mesh-terms=* Acetylcholine
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Diamines
* Disease Models, Animal
* G-Protein-Coupled Receptor Kinase 5
* Hippocampus
* Humans
* Lithium Chloride
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Mutation
* Neurons
* Parasympatholytics
* Phosphorylation
* tau Proteins

|full-text-url=https://sci-hub.do/10.1097/WNR.0000000000000142
}}
{{medline-entry
|title=Effects of curcuminoids identified in rhizomes of Curcuma longa on BACE-1 inhibitory and behavioral activity and lifespan of Alzheimer's disease Drosophila models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24597901
|abstract=Alzheimer's disease (AD) is the most common type of presenile and senile dementia. The human β-amyloid precursor cleavage enzyme (BACE-1) is a key enzyme responsible for amyloid plaque production, which implicates the progress and symptoms of AD. Here we assessed the anti-BACE-1 and behavioral activities of curcuminoids from rhizomes of Curcuma longa (Zingiberaceae), diarylalkyls curcumin (CCN), demethoxycurcumin (DMCCN), and bisdemethoxycurcumin (BDMCCN) against AD Drosophila melanogaster models. Neuro-protective ability of the curcuminoids was assessed using Drosophila melanogaster model system overexpressing BACE-1 and its substrate [[APP]] in compound eyes and entire neurons. Feeding and climbing activity, lifespan, and morphostructural changes in fly eyes also were evaluated. BDMCCN has the strongest inhibitory activity toward BACE-1 with 17 μM IC50, which was 20 and 13 times lower than those of CCN and DMCCN respectively. Overexpression of [[APP]]/BACE-1 resulted in the progressive and measurable defects in morphology of eyes and locomotion. Remarkably, supplementing diet with either 1 mM BDMCCN or 1 mM CCN rescued [[APP]]/BACE1-expressing flies and kept them from developing both morphological and behavioral defects. Our results suggest that structural characteristics, such as degrees of saturation, types of carbon skeleton and functional group, and hydrophobicity appear to play a role in determining inhibitory potency of curcuminoids on BACE-1. Further studies will warrant possible applications of curcuminoids as therapeutic BACE-1 blockers.
|mesh-terms=* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Animals
* Behavior, Animal
* Curcuma
* Curcumin
* Disease Models, Animal
* Drosophila
* Eye
* Female
* Humans
* Longevity
* Male
* Plant Extracts
* Rhizome

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946151
}}
{{medline-entry
|title=Age-dependent effects of valproic acid in Alzheimer's disease (AD) mice are associated with nerve growth factor ([[NGF]]) regulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24568732
|abstract=Alzheimer's disease (AD) is a progressive neurodegenerative disease that causes cognitive impairment. Major pathophysiological AD characteristics include numerous senile plaque, neurofibrillary tangles, and neuronal loss in the specific regions of patients' brains. In this study, we aimed to understand disease stage-dependent regulation of histone modification for the expression of specific markers in plasma and the hippocampus of in vivo AD model. Since the control of histone acetylation/deacetylation has been studied as one of major epigenetic regulatory mechanisms for specific gene expression, we detected the effects of histone deacetylase (HDAC) inhibitor on marker expression and neuroprotection in in vivo AD model mice. We determined the effects of valproic acid (VPA, HDAC inhibitor), on the levels of cytokines, secreted form of [[APP]] (s[[APP]]), nerve growth factor ([[NGF]]), and cognitive function in Tg6799 AD mice in three different disease stages (1month: pre-symptomatic; 5months: early symptomatic; and 10months: late-symptomatic stages). VPA decreased the mRNA levels of nuclear factor kappaB (NF-κB) and IL-1ß in the plasma of Tg6799 mice compared to vehicle control at 10months of age. VPA increased the protein levels of [[NGF]] in the hippocampus of Tg6799 mice at 5 and 10months of age. In addition, VPA decreased escape latencies of Tg6799 mice at 5 and 10months of age in Morris water maze assessment. Taken together, HDAC inhibition is a promising therapeutic target for AD and it needs to be considered in an age-dependent and/or stage-dependent manner. 
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Blotting, Western
* Disease Models, Animal
* Enzyme Inhibitors
* Hippocampus
* Immunohistochemistry
* Maze Learning
* Mice
* Mice, Transgenic
* Nerve Growth Factor
* Reverse Transcriptase Polymerase Chain Reaction
* Valproic Acid
|keywords=* AD
* NGF
* VPA
* aging
* cognitive improvement
* sAPP
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2014.02.012
}}
{{medline-entry
|title=Lessons from a [[BACE1]] inhibitor trial: off-site but not off base.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24530026
|abstract=Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein ([[APP]]) by β-site [[APP]]-cleaving enzyme ([[BACE1]]). Hence, [[BACE1]] activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of [[BACE1]] was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since [[BACE1]] knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-[[BACE1]] activity. We offer an alternative hypothesis, whereby anti-[[BACE1]] activity may induce apparent hepatotoxicity through inhibiting [[BACE1]]'s processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as [[BACE2]] or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic [[BACE1]] activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. 
|mesh-terms=* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Animals
* Aspartic Acid Endopeptidases
* Brain
* Clinical Trials as Topic
* Disease Models, Animal
* Heterocyclic Compounds, 2-Ring
* Humans
* Liver
* Mice, Knockout
* Models, Biological
* Nootropic Agents
* Picolinic Acids
* Protease Inhibitors
|keywords=* Aging
* Animal model
* Brain disorder
* CNS
* Dementia
* Demyelination
* Drug trial
* Human studies
* Liver damage
* Melatonin
* Neuronal death
* ROS
* Secretase
* Sialylation
* Side effects
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205206
}}
{{medline-entry
|title=A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24535457
|abstract=Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on [[APP]] metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of [[APP]] and its metabolites. 
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* European Continental Ancestry Group
* Genome-Wide Association Study
* HEK293 Cells
* Humans
* Membrane Proteins
* Peptide Fragments
* Polymorphism, Single Nucleotide

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418478
}}
{{medline-entry
|title=Early and sustained altered expression of aging-related genes in young 3xTg-AD mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24525730
|abstract=Alzheimer's disease (AD) is a multifactorial neurological condition associated with a genetic profile that is still not completely understood. In this study, using a whole gene microarray approach, we investigated age-dependent gene expression profile changes occurring in the hippocampus of young and old transgenic AD (3xTg-AD) and wild-type (WT) mice. The aim of the study was to assess similarities between aging- and AD-related modifications of gene expression and investigate possible interactions between the two processes. Global gene expression profiles of hippocampal tissue obtained from 3xTg-AD and WT mice at 3 and 12 months of age (m.o.a.) were analyzed by hierarchical clustering. Interaction among transcripts was then studied with the Ingenuity Pathway Analysis (IPA) software, a tool that discloses functional networks and/or pathways associated with sets of specific genes of interest. Cluster analysis revealed the selective presence of hundreds of upregulated and downregulated transcripts. Functional analysis showed transcript involvement mainly in neuronal death and autophagy, mitochondrial functioning, intracellular calcium homeostasis, inflammatory response, dendritic spine formation, modulation of synaptic functioning, and cognitive decline. Thus, overexpression of AD-related genes (such as mutant [[APP]], PS1, and hyperphosphorylated tau, the three genes that characterize our model) appears to favor modifications of additional genes that are involved in AD development and progression. The study also showed overlapping changes in 3xTg-AD at 3 m.o.a. and WT mice at 12 m.o.a., thereby suggesting altered expression of aging-related genes that occurs earlier in 3xTg-AD mice. 
|mesh-terms=* Age Factors
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Cluster Analysis
* Disease Models, Animal
* Female
* Gene Expression Profiling
* Gene Expression Regulation
* Gene Regulatory Networks
* Genetic Predisposition to Disease
* Hippocampus
* Humans
* Mice
* Mice, 129 Strain
* Mice, Inbred C57BL
* Mice, Transgenic
* Mutation
* Oligonucleotide Array Sequence Analysis
* Phenotype
* Polymerase Chain Reaction
* Presenilin-1
* Reproducibility of Results
* Time Factors
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944230
}}
{{medline-entry
|title=Mitochondrial oxygen consumption deficits in skeletal muscle isolated from an Alzheimer's disease-relevant murine model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24524276
|abstract=Age is considered a primary risk factor for neurodegenerative diseases including Alzheimer's disease (AD). It is also now well understood that mitochondrial function declines with age. Mitochondrial deficits have been previously assessed in brain from both human autopsy tissue and disease-relevant transgenic mice. Recently it has been recognized that abnormalities of muscle may be an intrinsic aspect of AD and might contribute to the pathophysiology. However, deficits in mitochondrial function have yet to be clearly assessed in tissues outside the central nervous system (CNS). In the present study, we utilized a well-characterized AD-relevant transgenic mouse strain to assess mitochondrial respiratory deficits in both brain and muscle. In addition to mitochondrial function, we assessed levels of transgene-derived amyloid precursor protein ([[APP]]) in homogenates isolated from brain and muscle of these AD-relevant animals. We now demonstrate that skeletal muscles isolated from these animals have differential levels of mutant full-length [[APP]] depending on muscle type. Additionally, isolated muscle fibers from young transgenic mice (3 months) have significantly decreased maximal mitochondrial oxygen consumption capacity compared to non-transgenic, age-matched mice, with similar deficits to those previously described in brain. This is the first study to directly examine mitochondrial function in skeletal muscle from an AD-relevant transgenic murine model. As with brain, these deficits in muscle are an early event, occurring prior to appearance of amyloid plaques.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Cells, Cultured
* Disease Models, Animal
* Humans
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria, Muscle
* Muscle, Skeletal
* Oxygen
* Oxygen Consumption

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930757
}}
{{medline-entry
|title=Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24440055
|abstract=Synapse number is the best indicator of cognitive impairment In Alzheimer's disease (AD), yet the respective contributions of Aβ and tau, particularly human wild-type tau, to synapse loss remain undefined. Here, we sought to elucidate the Aβ-dependent changes in wild-type human tau that trigger synapse loss and cognitive decline in AD by generating two novel transgenic mouse models. The first overexpresses floxed human [[APP]] with Swedish and London mutations under the thy1 promoter, and recapitulates important features of early AD, including accumulation of soluble Aβ and oligomers, but no plaque formation. Transgene excision via Cre-recombinase reverses cognitive decline, even at 18-months of age. Secondly, we generated a human wild-type tau-overexpressing mouse. Crossing of the two animals accelerates cognitive impairment, causes enhanced accumulation and aggregation of tau, and results in reduction of dendritic spines compared to single transgenic hTau or h[[APP]] mice. These results suggest that Aβ-dependent acceleration of wild-type human tau pathology is a critical component of the lasting changes to dendritic spines and cognitive impairment found in AD. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Brain
* CA1 Region, Hippocampal
* Cognition Disorders
* Dendritic Spines
* Disease Progression
* Humans
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Neurons
* Phosphorylation
* Proto-Oncogene Proteins c-fyn
* Pyramidal Cells
* Synapses
* tau Proteins
|keywords=* Alzheimer's disease
* Dendritic spines
* Transgenic
* Wild-type tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072239
}}
{{medline-entry
|title=Combined deletions of amyloid precursor protein and amyloid precursor-like protein 2 reveal different effects on mouse brain metal homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24448592
|abstract=Alterations to the expression of the Amyloid Precursor Protein ([[APP]]) and its paralogue Amyloid Precursor-Like Protein 2 ([[APLP2]]) affect metal homeostasis in vitro and in vivo. Analysis of the in vivo effects of the [[APP]] and [[APLP2]] knockouts on metal homeostasis has been restricted to [[APP]] and [[APLP2]] single knockout mice, and up to12 month old animals. To define the redundancy and inter-relationship between the [[APP]] and [[APLP2]] genes as regulators of metal homeostasis, and how this is influenced by aging, we investigated copper, iron, zinc and manganese levels in [[APP]] and [[APLP2]] single knockout mice as well as homozygous:hemizygous knockout mice at 3, 12 and 18 plus months of age. These studies identified age and genotype dependent changes in metal levels, and established differences in the relative roles played by [[APP]] and [[APLP2]] in modulating metal homeostasis. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Copper
* Gene Deletion
* Homeostasis
* Iron
* Manganese
* Metals, Heavy
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Zinc

|full-text-url=https://sci-hub.do/10.1039/c3mt00358b
}}
{{medline-entry
|title=Expression of amyloid-associated miRNAs in both the forebrain cortex and hippocampus of middle-aged rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24401368
|abstract=Aging is associated with the gradual cognitive decline and shows the typical senile plaque formation in the brain, which results from the aggregation of beta amyloid (Aβ) peptide following the abnormal proteolytic processing of amyloid precursor protein ([[APP]]) by β-secretase ([[BACE1]]) and γ-secretase. Accumulating evidence indicates that several microRNAs (miRNAs) are involved in the Alzheimer's disease (AD) by regulating the expression of [[APP]] and [[BACE1]] proteins. However, the cognitive ability and the expression profile of the [[APP]]- and [[BACE1]]-associated miRNAs in the middle-aged population are largely unknown. The learning and memory ability in rats were determined by Morris Water Maze test. The protein levels of [[APP]] and [[BACE1]] were detected by western blotting. The quantitative polymerase chain reaction was used to identify the miRNAs levels in forebrain cortex and the hippocampus. Middle-aged rats have declined learning ability without changes in the memory ability, and increased [[APP]] and [[BACE1]] protein expression in the forebrain cortex. Computational analysis using Targetscan and Pictar databases reveals that totally 4 predicted miRNAs have conserved binding site with [[APP]], namely miR-106b, -17-5p, -153, -101. All of them showed decreased expression in both the forebrain cortex and hippocampus. Among the 10 predicted miRNAs targeting [[BACE1]], different expression profiles were identified in the forebrain cortex (decreased: miR-9, -19a, -135a, -15b, -16, -195, -29c, -214; increased: miR-124; no change: miR-141) and the hippocampus (decreased: miR-9, -15b, -16, -195, -29c, -124; increased: miR-19a, -135a, -214, -141) in the middle-aged rats compared with the young rats. Our results provided the first evidence that middle-aged rats have begun displaying cognitive disability with abnormal expression of [[APP]]- and [[BACE1]]-related miRNAs in the hippocampus and forebrain cortex.
|mesh-terms=* Aging
* Amyloid
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Cognition
* Gene Expression Profiling
* Gene Expression Regulation, Developmental
* Hippocampus
* Male
* MicroRNAs
* RNA, Messenger
* Rats, Wistar

|full-text-url=https://sci-hub.do/10.1159/000356646
}}
{{medline-entry
|title=MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 ([[BACE1]]) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24352696
|abstract=Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein ([[APP]]). The rate-limiting step in the production of Aβ from [[APP]] is mediated by the β-site [[APP]]-cleaving enzyme 1 ([[BACE1]]). Dysregulation of [[BACE1]] levels leading to excess Aβ deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control [[BACE1]] expression is key to identifying novel drug targets central to the Aβ-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the [[BACE1]] 3'-UTR by in silico analyses. Co-transfection of miR-339-5p with a [[BACE1]] 3'-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of [[BACE1]] protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p [[BACE1]] 3'-UTR target sites in primary human brain cultures significantly elevated [[BACE1]] expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates [[BACE1]] expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target. 
|mesh-terms=* 3' Untranslated Regions
* Aged
* Aged, 80 and over
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Argonaute Proteins
* Aspartic Acid Endopeptidases
* Base Sequence
* Brain
* Cell Line, Tumor
* Cell Shape
* Cells, Cultured
* Computational Biology
* Conserved Sequence
* Demography
* Down-Regulation
* Female
* Gene Knockdown Techniques
* Humans
* Male
* MicroRNAs
* Molecular Sequence Data
* Protein Binding
* Reproducibility of Results
* Time Factors
|keywords=* Aging
* Alzheimer Disease
* Dementia
* Gene Regulation
* Human Brain Tissue
* Human Neuron
* MicroRNA
* Noncoding RNA
* Secretases
* β-Peptide
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931075
}}
{{medline-entry
|title=The effects of dietary restriction and aging on amyloid precursor protein and presenilin-1 mRNA and protein expression in rat brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24346258
|abstract=The objective of this study was to examine the effects of aging and long-term dietary restriction (DR) on the level of amyloid precursor protein ([[APP]]) and presenilin-1 (PS-1), proteins that are critically involved in Alzheimer's disease. Changes in mRNA and protein expression were assessed by real-time PCR and western blot analysis during aging and long-term DR in the cortex and hippocampus of 6-, 12-, 18-, and 24-month-old rats. Prominent regional changes in expression were observed in response to aging and DR. Although the hippocampus displayed significant alterations in [[APP]] mRNA and protein expression and no significant changes in PS-1 expression, an opposite pattern was observed in the cortex. DR counteracted the age-related changes in [[APP]] mRNA expression in both structures of old animals. The observed DR-induced increase in mRNA levels in the hippocampus was accompanied by an increase in the level of full-length protein [[APP]]. These results indicate that although both structures are very sensitive to aging, a specific spatial pattern of changes in [[APP]] and PS-1 occurs during aging. Furthermore, these findings provide evidence that DR can affect [[APP]] and PS-1 expression in a manner consistent with its proposed 'antiaging' effect. 
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Animals
* Caloric Restriction
* Cerebral Cortex
* Hippocampus
* Male
* Presenilin-1
* RNA, Messenger
* Rats
* Rats, Wistar

|full-text-url=https://sci-hub.do/10.1097/WNR.0000000000000107
}}
{{medline-entry
|title=Rheb GTPase regulates β-secretase levels and amyloid β generation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24368770
|abstract=The β-site amyloid precursor protein ([[APP]])-cleaving enzyme 1 (β-secretase, [[BACE1]]) initiates amyloidogenic processing of [[APP]] to generate amyloid β (Aβ), which is a hallmark of Alzheimer disease (AD) pathology. Cerebral levels of [[BACE1]] are elevated in individuals with AD, but the molecular mechanisms are not completely understood. We demonstrate that Rheb GTPase (Ras homolog enriched in brain), which induces mammalian target of rapamycin (mTOR) activity, is a physiological regulator of [[BACE1]] stability and activity. Rheb overexpression depletes [[BACE1]] protein levels and reduces Aβ generation, whereas the RNAi knockdown of endogenous Rheb promotes [[BACE1]] accumulation, and this effect by Rheb is independent of its mTOR signaling. Moreover, GTP-bound Rheb interacts with [[BACE1]] and degrades it through proteasomal and lysosomal pathways. Finally, we demonstrate that Rheb levels are down-regulated in the AD brain, which is consistent with an increased [[BACE1]] expression. Altogether, our study defines Rheb as a novel physiological regulator of [[BACE1]] levels and Aβ generation, and the Rheb-[[BACE1]] circuitry may have a role in brain biology and disease. 
|mesh-terms=* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Brain
* Gene Expression Regulation, Enzymologic
* HEK293 Cells
* Humans
* Mice
* Monomeric GTP-Binding Proteins
* Neuropeptides
* Protein Binding
* Proteolysis
* Ras Homolog Enriched in Brain Protein
|keywords=* Aging
* Amyloid
* GTPase
* Protein Stability
* Secretases
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937651
}}
{{medline-entry
|title=The type of Aβ-related neuronal degeneration differs between amyloid precursor protein ([[APP]]23) and amyloid β-peptide ([[APP]]48) transgenic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24252227
|abstract=The deposition of the amyloid β-peptide (Aβ) in the brain is one of the hallmarks of Alzheimer's disease (AD). It is not yet clear whether Aβ always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: [[APP]]48 and [[APP]]23 mice. The [[APP]]48 mouse expresses Aβ1-42 with a signal sequence in neurons. These animals produce intracellular Aβ independent of amyloid precursor protein ([[APP]]) but do not develop extracellular Aβ plaques. The [[APP]]23 mouse overexpresses human [[APP]] with the Swedish mutation (KM670/671NL) in neurons and produces [[APP]]-derived extracellular Aβ plaques and intracellular Aβ aggregates. Tracing of commissural neurons in layer III of the frontocentral cortex with the DiI tracer revealed no morphological signs of dendritic degeneration in [[APP]]48 mice compared to littermate controls. In contrast, the dendritic tree of highly ramified commissural frontocentral neurons was altered in 15-month-old [[APP]]23 mice. The density of asymmetric synapses in the frontocentral cortex was reduced in 3- and 15-month-old [[APP]]23 but not in 3- and 18-month-old [[APP]]48 mice. Frontocentral neurons of 18-month-old [[APP]]48 mice showed an increased proportion of altered mitochondria in the soma compared to wild type and [[APP]]23 mice. Aβ was often seen in the membrane of neuronal mitochondria in [[APP]]48 mice at the ultrastructural level. These results indicate that [[APP]]-independent intracellular Aβ accumulation in [[APP]]48 mice is not associated with dendritic and neuritic degeneration but with mitochondrial alterations whereas [[APP]]-derived extra- and intracellular Aβ pathology in [[APP]]23 mice is linked to dendrite degeneration and synapse loss independent of obvious mitochondrial alterations. Thus, Aβ aggregates in [[APP]]23 and [[APP]]48 mice induce neurodegeneration presumably by different mechanisms and [[APP]]-related production of Aβ may, thereby, play a role for the degeneration of neurites and synapses.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Disease Models, Animal
* Female
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria
* Mutation
* Neurites
* Neurodegenerative Diseases
* Neurons
* Peptide Fragments
* Synapses

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046770
}}
{{medline-entry
|title=The airbag problem-a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24252346
|abstract=For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that [[APP]] and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Humans
* Neurons

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893418
}}
{{medline-entry
|title=[[BIN1]] is decreased in sporadic but not familial Alzheimer's disease or in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24205320
|abstract=Bridging integrator 1 ([[BIN1]]) has been implicated in sporadic Alzheimer's disease (AD) by a number of genome wide association studies (GWAS) in a variety of populations. Here we measured [[BIN1]] in frontal cortex samples from 24 sporadic AD and 24 age-matched non-dementia brains and correlated the expression of this protein with markers of AD. [[BIN1]] was reduced by 87% (p=0.007) in sporadic AD compared to non-dementia controls, but [[BIN1]] in sporadic AD did not correlate with soluble Aβ (r(s)=-0.084, p=0.698), insoluble Aβ (r(s)=0.237, p=0.269), Aβ plaque load (r(s)=0.063, p=0.771) or phospho-tau load (r(s)=-0.160, p=0.489). In contrast to our findings in sporadic AD, [[BIN1]] was unchanged in the hippocampus from 6 cases of familial AD compared to 6 age-matched controls (p=0.488). [[BIN1]] declined with age in a cohort of non-dementia control cases between 25 and 88 years but the correlation was not significant (rs=-0.449, p=0.081). Although [[BIN1]] is known to have a role in endocytosis, and the processing of the amyloid precursor protein ([[APP]]) to form amyloid-β (Aβ) peptides is dependent on endocytosis, knockdown of [[BIN1]] by targeted siRNA or the overexpression of [[BIN1]] in a human neuroblastoma cell line (SH-SY5Y) had no effect on [[APP]] processing. These data suggest that the alteration in [[BIN1]] is involved in the pathogenesis of sporadic, but not familial AD and is not a consequence of AD neurodegeneration or the ageing process, a finding in keeping with the numerous GWAS that implicate [[BIN1]] in sporadic AD. However, the mechanism of its contribution remains to be established.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Adult
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Cell Line, Tumor
* Female
* Gene Expression Regulation
* Gene Knockdown Techniques
* Humans
* Male
* Middle Aged
* Nuclear Proteins
* Tumor Suppressor Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804620
}}
{{medline-entry
|title=Absence of A673T variant in [[APP]] gene indicates an alternative protective mechanism contributing to longevity in Chinese individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24126161
|abstract=A673T, a rare variant in the amyloid-β precursor protein gene, shows a protective potential against Alzheimer's disease (AD) and age-related cognitive decline in an Icelandic population. Although A673T was observed independently in a Finnish population, this variant was absent in 8721 Asian subjects. The conflicting observations suggest that the contribution of A673T may be confined to Europeans and Americans rather than Asians. Nevertheless, A673T confers a protective function against AD and thus may be observed only in longevity subjects; thus it is not surprising to see its absence when the general populations or the patient cohorts were considered. To test whether the A673T contributes to the Chinese population, 1237 healthy longevity subjects (mean age 96.9 years) and 1404 matched younger controls (mean age 44.2 years) were genotyped for the variant. Our study failed to observe this variant in either the longevity subjects or the controls. Given the previous observation from Asians, our results suggest that the A673T variant is not involved in longevity in Chinese individuals; some other protective mechanisms may contribute to a lower incidence of AD in Chinese nonagenerians and centenarians. 
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Asian Continental Ancestry Group
* Female
* Genetic Variation
* Humans
* Longevity
* Male
* Middle Aged
|keywords=* A673T
* Alzheimer's disease
* Amyloid precursor protein
* Chinese
* Longevity
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2013.09.023
}}
{{medline-entry
|title=The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24071439
|abstract=Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein ([[APP]]) expression, [[APP]] processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.
|mesh-terms=* Alzheimer Disease
* Animals
* Biomarkers
* Humans
* Mitochondria
* Models, Biological
* Signal Transduction
|keywords=* Aging
* Alzheimer's disease
* Amyloid
* Brain
* Dementia
* Mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962811
}}
{{medline-entry
|title=Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged [[APP]]/PS1 mice, a model of Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23973293
|abstract=Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza(®)) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall [[APP]] and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old [[APP]]swe/PS1ΔE9 ([[APP]]/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-month-old [[APP]]/PS1 and littermate control mice were injected with Liraglutide (25 nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in [[APP]]/PS1 mice compared with [[APP]]/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in [[APP]]/PS1 liraglutide-treated mice compared with [[APP]]/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain [[APP]] and beta-amyloid oligomer levels were reduced in Liraglutide-treated [[APP]]/PS1 mice while [[IDE]] levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but also can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Cell Count
* Disease Models, Animal
* Glucagon-Like Peptide 1
* Inflammation
* Liraglutide
* Long-Term Potentiation
* Male
* Memory
* Memory Disorders
* Mice
* Mice, Transgenic
* Nerve Degeneration
* Neuroprotective Agents
* Plaque, Amyloid
* Stem Cells
* Synapses
|keywords=* Cognition
* GLP-1
* Incretins
* Inflammation
* Insulin
* Memory
* Neurodegeneration
* Neuroprotection
* Stem cells
* Synapse
|full-text-url=https://sci-hub.do/10.1016/j.neuropharm.2013.08.005
}}
{{medline-entry
|title=Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23955715
|abstract=Strong epidemiological and experimental evidence indicate that hypertension in the elderly predisposes to the development of Alzheimer's disease (AD), but the underlying mechanisms remain elusive. The present study was designed to characterize the additive/synergistic effects of hypertension and aging on the expression of genes involved in β-amyloid generation and AD in the hippocampus, an area of brain contributing to higher cognitive function, which is significantly affected by AD both in humans and in mouse models of the disease. To achieve that goal, we induced hypertension in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic (4 wk) infusion of angiotensin II and assessed changes in hippocampal mRNA expression of genes involved in amyloid precursor protein ([[APP]])-dependent signaling, [[APP]] cleavage, Aβ processing and Aβ-degradation, synaptic function, dysregulation of microtubule-associated τ protein, and apolipoprotein-E signaling. Aged hypertensive mice exhibited spatial memory impairments in the Y-maze and impaired performance in the novel object recognition assay. Surprisingly, hypertension in aging did not increase the expression of [[APP]], β- and γ-secretases, or genes involved in tauopathy. These genes are all involved in the early onset form of AD. Yet, hypertension in aging was associated with changes in hippocampal expression of [[APP]] binding proteins, e.g., [Mint3/amyloid β A4 precursor protein-binding family A member 3 (APBA3), Fe65/amyloid β A4 precursor protein-binding family B member 1 (APBB1)], amyloid β (A4) precursor-like protein 1 (APLP1), muscarinic M1 receptor, and serum amyloid P component, all of which may have a role in the pathogenesis of late-onset AD. The hippocampal gene expression signature observed in aged hypertensive mice in the present study provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of AD. 
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Disease Models, Animal
* Gene Expression
* Hippocampus
* Hypertension
* Male
* Mice
* Mice, Inbred C57BL
* Nerve Tissue Proteins
* Nuclear Proteins
* RNA, Messenger
* Receptor, Muscarinic M1
* Serum Amyloid P-Component
|keywords=* Alzheimer's disease
* dementia
* hypertension
* senescence
* tauopathy
* vascular aging
* vascular cognitive impairment
* β-amyloid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798788
}}
{{medline-entry
|title=Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23863834
|abstract=Altered concentrations of amyloid-β (Aβ) peptide and Tau protein in the cerebrospinal fluid (CSF) are thought to be predictive markers for Alzheimer's disease (AD). Transgenic mice overexpressing human amyloid precursor protein ([[APP]]) have been used to model Aβ pathology, but concomitant changes in Aβ and Tau in CSF have been less well studied. We measured Aβ and Tau in the brains and CSF of two well-characterized transgenic mouse models of AD: one expressing human [[APP]] carrying the Swedish mutation ([[APP]]23) and the other expressing mutant human [[APP]] and mutant human presenilin-1 ([[APP]]PS1). Both mouse models exhibit Aβ deposition in the brain, but with different onset and progression trajectories. We found an age-related 50 to 80% decrease in Aβ42 peptide in mouse CSF and a smaller decrease in Aβ40, both inversely correlated with the brain Aβ load. Surprisingly, the same mice showed a threefold increase in total endogenous murine Tau in CSF at the stages when Aβ pathology became prominent. The results mirror the temporal sequence and magnitude of Aβ and Tau changes in the CSF of patients with sporadic and dominantly inherited AD. This observation indicates that [[APP]] transgenic mice may be useful as a translational tool for predicting changes in Aβ and Tau markers in the CSF of AD patients. These findings also suggest that [[APP]] transgenic mouse models may be useful in the search for new disease markers for AD. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Disease Progression
* Female
* Humans
* Male
* Mice
* Mice, Transgenic
* alpha-Synuclein
* tau Proteins

|full-text-url=https://sci-hub.do/10.1126/scitranslmed.3006446
}}
{{medline-entry
|title=Antisense directed against PS-1 gene decreases brain oxidative markers in aged senescence accelerated mice (SAMP8) and reverses learning and memory impairment: a proteomics study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23777706
|abstract=Amyloid β-peptide (Aβ) plays a central role in the pathophysiology of Alzheimer's disease (AD) through the induction of oxidative stress. This peptide is produced by proteolytic cleavage of amyloid precursor protein ([[APP]]) by the action of β- and γ-secretases. Previous studies demonstrated that reduction of Aβ, using an antisense oligonucleotide (AO) directed against the Aβ region of [[APP]], reduced oxidative stress-mediated damage and prevented or reverted cognitive deficits in senescence-accelerated prone mice (SAMP8), a useful animal model for investigating the events related to Aβ pathology and possibly to the early phase of AD. In the current study, aged SAMP8 were treated by AO directed against PS-1, a component of the γ-secretase complex, and tested for learning and memory in T-maze foot shock avoidance and novel object recognition. Brain tissue was collected to identify the decrease of oxidative stress and to evaluate the proteins that are differently expressed and oxidized after the reduction in free radical levels induced by Aβ. We used both expression proteomics and redox proteomics approaches. In brain of AO-treated mice a decrease of oxidative stress markers was found, and the proteins identified by proteomics as expressed differently or nitrated are involved in processes known to be impaired in AD. Our results suggest that the treatment with AO directed against PS-1 in old SAMP8 mice reverses learning and memory deficits and reduces Aβ-mediated oxidative stress with restoration to the normal condition and identifies possible pharmacological targets to combat this devastating dementing disease. 
|mesh-terms=* Alzheimer Disease
* Animals
* Blotting, Western
* Disease Models, Animal
* Electrophoresis, Gel, Two-Dimensional
* Hippocampus
* Immunoprecipitation
* Mass Spectrometry
* Maze Learning
* Mice
* Oligonucleotides, Antisense
* Oxidative Stress
* Presenilin-1
* Proteomics
|keywords=* 5-bromo-4-chloro-3-indolyl phosphate/nitrotetrazolium blue chloride
* AATC
* AD
* AO
* APP
* Alzheimer's disease
* Amyloid precursor protein
* Amyloid β-peptide
* Aβ
* BCIP/NBT
* CRMP-1
* CRMP-2
* ES1
* ES1 protein homolog
* FAD
* IDH3A, isocitrate dehydrogenase subunit alpha
* L-lactate dehydrogenase
* LDH
* M1/M2 KPYM
* MCI
* NAD
* NFT
* NSF
* PDHA1 and PDH
* PS-1
* PS-2
* SAM
* SNAPs
* Senescence accelerated mouse
* TPI
* V-ATPase
* amyloid precursor protein
* amyloid β-peptide
* antisense oligonucleotide
* aspartate aminotransferase
* dihydropyrimidinase-related protein 1
* dihydropyrimidinase-related protein 2
* familial Alzheimer's disease
* intracellular neurofibrillary tangles
* isocitrate dehydrogenase
* isoform M1 pyruvate kinase isozymes
* mild cognitive impairment
* presenilin-1
* presenilin-2
* pyruvate dehydrogenase E1 component subunit alpha and beta
* senescence accelerated mouse
* soluble N-ethylmaleimide-sensitive factor attachment proteins
* triosephosphate isomerase
* vacuolar-type H -ATPase
* vesicle-fusing ATPase/vesicular-fusion protein NSF
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855183
}}
{{medline-entry
|title=Swedish mutant [[APP]] suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23649480
|abstract=Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein ([[APP]]) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the [[APP]] gene identified in early-onset AD patients are believed to cause AD. But little is known about [[APP]]'s role in bone remodeling. Here, we present evidence for Swedish mutant [[APP]] ([[APP]]swe) in suppression of OB differentiation and function in culture and in mouse. [[APP]] expression in BMSCs increases during aging. Ubiquitous expression of [[APP]]swe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of [[APP]]swe in mature OB-lineage cells in Tg[[APP]]swe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for [[APP]]swe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in Tg[[APP]]swe-Ocn mice, implying that [[APP]]swe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie [[APP]]swe-induced osteoporotic deficits. Taken together, these results demonstrate a role for [[APP]]swe in suppressing OB differentiation and bone formation, implicate [[APP]]swe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research. 
|mesh-terms=* Acetylcysteine
* Acid Phosphatase
* Adipogenesis
* Aging
* Amyloid beta-Peptides
* Animals
* Animals, Newborn
* Bone Resorption
* Bone and Bones
* Cell Differentiation
* Cell Lineage
* Cells, Cultured
* Cricetinae
* Humans
* Isoenzymes
* Mesenchymal Stem Cells
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Mutation
* Organ Size
* Osteoblasts
* Osteogenesis
* Osteoporosis
* Tartrate-Resistant Acid Phosphatase
|keywords=* ALZHEIMER'S DISEASE
* APP
* NAC
* OSTEOBLAST
* OSTEOPOROSIS
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104794
}}
{{medline-entry
|title=Non-invasive infra-red therapy (1072 nm) reduces β-amyloid protein levels in the brain of an Alzheimer's disease mouse model, TASTPM.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23603448
|abstract=Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and common cause of dementias in the Western world. This study investigated the expression profile of heat-shock proteins (HSPs) involved in maintaining healthy neurons in the TASTPM AD mouse model, and whether chronic treatment with 1072 nm infra-red (IR1072) modified the expression profiles of HSPs and amyloidopathy in female TASTPM mice. Quantitative immunoblotting and immunohistochemistry were used to examine the expression of proteins such as HSPs, phosphorylated tau (tau-P), amyloid precursor protein ([[APP]]), β-amyloid1-40 (Aβ), and Aβ1-42. TASTPM mice at 3, 7 and 12 months were investigated as well as female TASTPM mice which had undergone a chronic, 5 month, IR1072 treatment. During the first 12 months of age, a critical period of AD progression, reduced HSP40 and HSP105 were observed. αB-crystallin, Aβ1-42 and tau-P increased over this period, particularly between 3 and 7 months. Chronic IR1072 treatment of female TASTPM mice elicited significant increases in HSP60, 70 and 105 and phosphorylated-HSP27 (P-HSP27) (50-139%), together with a concomitant profound decrease in αB-crystallin, [[APP]], tau-P, Aβ1-40 and Aβ1-42 (43-81%) protein levels at 7 months of age. Furthermore, IR1072 treatment elicited a modest, but significant, reduction in Aβ1-42 plaques in the cerebral cortex. IR1072 treatment provides a novel non-invasive and safe way to upregulate a panel of stress response proteins in the brain, known to both reduce protein aggregation and neuronal apoptosis. This approach recently entered clinical trials for AD in the USA, and may provide a novel disease modifying therapy for a range of neuropathologies.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Disease Models, Animal
* Female
* HSP110 Heat-Shock Proteins
* HSP40 Heat-Shock Proteins
* Heat-Shock Proteins
* Infrared Rays
* Male
* Mice
* Mice, Transgenic
* Plaque, Amyloid
* Transcriptome
* alpha-Crystallin B Chain

|full-text-url=https://sci-hub.do/10.1016/j.jphotobiol.2013.02.015
}}
{{medline-entry
|title=The retinoic acid receptor agonist Am80 increases hippocampal [[ADAM10]] in aged SAMP8 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23624141
|abstract=The retinoic acid (RA, a vitamin A metabolite) receptor (RAR) is a transcription factor. Vitamin A/RA administration improves the Alzheimer's disease (AD)- and age-related attenuation of memory/learning in mouse models. Recently, a disintegrin and metalloproteinase domain-containing protein 10 ([[ADAM10]]) was identified as a key molecule in RA-mediated anti-AD mechanisms. We investigated the effect of chronic administration of the RAR agonist Am80 (tamibarotene) on [[ADAM10]] expression in senescence-accelerated mice (SAMP8). Moreover, we estimated changes in the expression of the amyloid precursor protein ([[APP]]), amyloid beta (Aβ), and hairy/enhancer of split (Hes), which are mediated by [[ADAM10]]. Spatial working memory and the levels of a hippocampal proliferation marker (Ki67) were also assessed in these mice. [[ADAM10]] mRNA and protein expression was significantly reduced in the hippocampus of 13-month-old SAMP8 mice; their expression improved significantly after Am80 administration. Further, after Am80 administration, the expression levels of Hes5 and Ki67 were restored and the deterioration of working memory was suppressed, whereas [[APP]] and Aβ levels remained unchanged. Our results suggest that Am80 administration effectively improves dementia by activating the hippocampal [[ADAM10]]-Notch-Hes5 proliferative pathway.
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* Aging
* Amyloid Precursor Protein Secretases
* Animals
* Basic Helix-Loop-Helix Transcription Factors
* Benzoates
* Cell Proliferation
* Gene Expression Regulation
* Hippocampus
* Ki-67 Antigen
* Maze Learning
* Membrane Proteins
* Memory, Short-Term
* Mice
* Mice, Mutant Strains
* RNA, Messenger
* Receptors, Retinoic Acid
* Repressor Proteins
* Tetrahydronaphthalenes
* Time Factors

|full-text-url=https://sci-hub.do/10.1016/j.neuropharm.2013.04.009
}}
{{medline-entry
|title=Spatial learning impairments in PLB1Triple knock-in Alzheimer mice are task-specific and age-dependent.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23535719
|abstract=We recently generated an advanced mouse model of Alzheimer's disease (AD) by targeted knock-in of single-copy mutated human amyloid precursor-protein ([[APP]]) and tau genes, crossed with a non-symptomatic presenilin (PS1A246E) over-expressing mouse line. These PLB1Triple mice presented with age-dependent and AD-relevant phenotypes. Homozygous PLB1Triple mice aged 4-12 months were assessed here in a battery of spatial learning tasks: Exp.1 radial-arm water maze (spatial reference and working memory) Exp.2 open-field water maze (spatial reference memory); Exp.3 home cage observation system with spatial learning (IntelliCage); Exp.4 spontaneous object recognition (SOR; novel object and spatial object shift). A separate test with high-expression transgenic [[APP]] mice matching the design of experiment 1 was also performed. Spatial deficits in PLB1Triple mice were confirmed at 12, but not 4 months in both water maze tasks. PS[[APP]] mice, by contrast, presented with severe yet non-progressive spatial learning deficits already at 4 months. During tests of spatial learning in SOR and IntelliCage, PLB1Triple mice neither acquired the location of the water-rewarded corner, nor recognize novel or spatially shifted objects at 4 months, indicating these protocols to be more sensitive than the water maze. Collectively and in line with AD symptomatology, PLB1Triple mice present with a graded and progressive age-dependent loss of spatial memory that can be revealed by the use of a battery of tasks. With the emergence of subtle deficits progressively increasing in severity, PLB1Triple mice may offer a more patho-physiologically relevant model of dementia than aggressive expression models. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Behavior, Animal
* Brain
* Calcium-Calmodulin-Dependent Protein Kinase Type 2
* Disease Models, Animal
* Female
* Gene Knock-In Techniques
* Humans
* Male
* Maze Learning
* Memory
* Mice
* Mice, Transgenic
* Presenilins
* Promoter Regions, Genetic
* tau Proteins

|full-text-url=https://sci-hub.do/10.1007/s00018-013-1314-4
}}
{{medline-entry
|title=The senescence hypothesis of disease progression in Alzheimer disease: an integrated matrix of disease pathways for FAD and SAD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23546742
|abstract=Alzheimer disease (AD) is a progressive, neurodegenerative disease characterised in life by cognitive decline and behavioural symptoms and post-mortem by the neuropathological hallmarks including the microtubule-associated protein tau-reactive tangles and neuritic plaques and amyloid-beta-protein-reactive senile plaques. Greater than 95 % of AD cases are sporadic (SAD) with a late onset and <5 % of AD cases are familial (FAD) with an early onset. FAD is associated with various genetic mutations in the amyloid precursor protein ([[APP]]) and the presenilins (PS)1 and PS2. As yet, no disease pathway has been fully accepted and there are no treatments that prevent, stop or reverse the cognitive decline associated with AD. Here, we review and integrate available environmental and genetic evidence associated with all forms of AD. We present the senescence hypothesis of AD progression, suggesting that factors associated with AD can be seen as partial stressors within the matrix of signalling pathways that underlie cell survival and function. Senescence pathways are triggered when stressors exceed the cells ability to compensate for them. The [[APP]] proteolytic system has many interactions with pathways involved in programmed senescence and [[APP]] proteolysis can both respond to and be driven by senescence-associated signalling. Disease pathways associated with sporadic disease may be different to those involving familial genetic mutations. The interpretation we provide strongly points to senescence as an additional underlying causal process in dementia progression in both SAD and FAD via multiple disease pathways.
|mesh-terms=* Aging
* Alzheimer Disease
* Disease Progression
* Humans
* Models, Biological
* Nerve Degeneration
* Neurons

|full-text-url=https://sci-hub.do/10.1007/s12035-013-8445-3
}}
{{medline-entry
|title=Aβ43 is the earliest-depositing Aβ species in [[APP]] transgenic mouse brain and is converted to Aβ41 by two active domains of [[ACE]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23562443
|abstract=Amyloid-β protein (Aβ) varies in length at its carboxyl terminus. The longer Aβ species, Aβ43 and Aβ42, are highly amyloidogenic and deposit more frequently than Aβ40 in the brain of Alzheimer disease (AD) patients. However, the characterization of Aβ43 deposition in the brain and the relationship between Aβ43 and Aβ42 or Aβ40 remain unclear. We provide evidence that Aβ43 deposition appears earlier than Aβ42 and Aβ40 deposition in the brain of mutant amyloid precursor protein transgenic ([[APP]]tg) mice, suggesting that Aβ43 is the earliest-depositing species. In addition, we found increased Aβ43 levels and Aβ43/Aβ42 ratios in the serum of AD patients, suggesting their use as diagnostic blood biomarkers for AD. We further show that angiotensin-converting enzyme ([[ACE]]) converts Aβ43 to Aβ41. Notably, this Aβ43-to-Aβ41 converting activity requires two active domains of [[ACE]]. Inhibition of [[ACE]] activity significantly enhanced Aβ43 deposition in [[APP]]tg mouse brain. Our results suggest that Aβ43 is the earliest-depositing species in brain parenchyma and that Aβ43 may trigger later Aβ42 and Aβ40 deposition or may be converted to Aβ42 and Aβ40 plaques. Activities of both [[ACE]] domains may be important for reducing Aβ43 levels in serum and reducing brain Aβ43 deposition.
|mesh-terms=* Aged
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Angiotensin-Converting Enzyme Inhibitors
* Animals
* Biomarkers
* Brain
* Captopril
* Case-Control Studies
* Disease Progression
* Humans
* Mice
* Mice, Transgenic
* Mutation
* Peptide Fragments
* Peptidyl-Dipeptidase A
* Presenilins

|full-text-url=https://sci-hub.do/10.1016/j.ajpath.2013.01.053
}}
{{medline-entry
|title=Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid-β from the mouse brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23413811
|abstract=Development of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) is associated with failure of elimination of amyloid-β (Aβ) from the brain along perivascular basement membranes that form the pathways for drainage of interstitial fluid and solutes from the brain. In transgenic [[APP]] mouse models of AD, the severity of cerebral amyloid angiopathy is greater in the cerebral cortex and hippocampus, intermediate in the thalamus, and least in the striatum. In this study we test the hypothesis that age-related regional variation in (1) vascular basement membranes and (2) perivascular drainage of Aβ contribute to the different regional patterns of CAA in the mouse brain. Quantitative electron microscopy of the brains of 2-, 7-, and 23-month-old mice revealed significant age-related thickening of capillary basement membranes in cerebral cortex, hippocampus, and thalamus, but not in the striatum. Results from Western blotting and immunocytochemistry experiments showed a significant reduction in collagen IV in the cortex and hippocampus with age and a reduction in laminin and nidogen 2 in the cortex and striatum. Injection of soluble Aβ into the hippocampus or thalamus showed an age-related reduction in perivascular drainage from the hippocampus but not from the thalamus. The results of the study suggest that changes in vascular basement membranes and perivascular drainage with age differ between brain regions, in the mouse, in a manner that may help to explain the differential deposition of Aβ in the brain in AD and may facilitate development of improved therapeutic strategies to remove Aβ from the brain in AD.
|mesh-terms=* Aging
* Amyloid beta-Peptides
* Animals
* Basement Membrane
* Calcium-Binding Proteins
* Capillaries
* Cell Adhesion Molecules
* Cerebral Amyloid Angiopathy
* Cerebral Cortex
* Collagen Type IV
* Corpus Striatum
* Extracellular Fluid
* Female
* Hippocampus
* Humans
* Laminin
* Male
* Membrane Glycoproteins
* Mice
* Mice, Transgenic
* Organ Specificity
* Thalamus

|full-text-url=https://sci-hub.do/10.1111/acel.12045
}}
{{medline-entry
|title=Identification of biomarkers of human skin ageing in both genders. Wnt signalling - a label of skin ageing?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23226273
|abstract=The goal of our work has been to investigate the mechanisms of gender-independent human skin ageing and examine the hypothesis of skin being an adequate model of global ageing. For this purpose, whole genome gene profiling was employed in sun-protected skin obtained from European Caucasian young and elderly females (mean age 26.7±4 years [n1 = 7] and 70.75±3.3 years [n2 = 4], respectively) and males (mean age 25.8±5.2 years [n3 = 6] and 76±3.8 years [n4 = 7], respectively) using the Illumina array platform. Confirmation of gene regulation was performed by real-time RT-PCR and immunohistochemistry. 523 genes were significantly regulated in female skin and 401 genes in male skin for the chosen criteria. Of these, 183 genes exhibited increased and 340 decreased expression in females whereas 210 genes showed increased and 191 decreased expression in males with age. In total, 39 genes were common in the target lists of significant regulated genes in males and females. 35 of these genes showed increased (16) or decreased (19) expression independent of gender. Only 4 overlapping genes (OR52N2, F6FR1OP2, [[TUBAL3]] and STK40) showed differential regulation with age. Interestingly, Wnt signalling pathway showed to be significantly downregulated in aged skin with decreased gene and protein expression for males and females, accordingly. In addition, several genes involved in central nervous system (CNS) ageing (f.i. [[APP]], TAU) showed to be expressed in human skin and were significanlty regulated with age. In conclusion, our study provides biomarkers of endogenous human skin ageing in both genders and highlight the role of Wnt signalling in this process. Furthermore, our data give evidence that skin could be used as a good alternative to understand ageing of different tissues such as CNS.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Central Nervous System
* Female
* Gene Expression Profiling
* Gene Expression Regulation
* Genome-Wide Association Study
* Humans
* Immunohistochemistry
* Male
* Oligonucleotide Array Sequence Analysis
* Real-Time Polymerase Chain Reaction
* Sex Factors
* Skin Aging
* Sunlight
* Transcriptome
* Ultraviolet Rays
* Wnt Signaling Pathway

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511529
}}
{{medline-entry
|title=Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23225010
|abstract=Alzheimer's disease (AD) is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms, mostly affecting medial temporal lobe and associative neocortical structures. Neuritic plaques and neurofibrillary tangles represent the pathological hallmarks of AD, and are respectively related to the accumulation of the amyloid-beta peptide (Aβ) in brain tissues, and to cytoskeletal changes that arise from the hyperphosphorylation of microtubule-associated Tau protein in neurons. According to the amyloid hypothesis of AD, the overproduction of Aβ is a consequence of the disruption of homeostatic processes that regulate the proteolytic cleavage of the amyloid precursor protein ([[APP]]). Genetic, age-related and environmental factors contribute to a metabolic shift favoring the amyloidogenic processing of [[APP]] in detriment of the physiological, secretory pathway. Aβ peptides are generated by the successive cleavage of [[APP]] by beta-secretase (BACE-1) and gamma-secretase, which has been recently characterized as part of the presenilin complex. Among several beta-amyloid isoforms that bear subtle differences depending on the number of C-terminal amino acids, Aβ                         (1-42) plays a pivotal role in the pathogenesis of AD. The neurotoxic potential of the Aβ peptide results from its biochemical properties that favor aggregation into insoluble oligomers and protofibrils. These further originate fibrillary Aβ species that accumulate into senile and neuritic plaques. These processes, along with a reduction of Aβ clearance from the brain, leads to the extracellular accumulation of Aβ, and the subsequent activation of neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and cellular death. Intracerebral amyloidosis develops in AD patients in an age-dependent manner, but recent evidence indicate that it may be observed in some subjects as early as in the third or fourth decades of life, with increasing magnitude in late middle age, and highest estimates in old age. According to recent propositions, three clinical phases of Alzheimer's disease may be defined: (i) pre-symptomatic (or pre-clinical) AD, which may last for several years or decades until the overproduction and accumulation of Aβ in the brain reaches a critical level that triggers the amyloid cascade; (ii) pre-dementia phase of AD (compatible with the definition of progressive, amnestic mild cognitive impairment), in which early-stage pathology is present, ranging from mild neuronal dystrophy to early-stage Braak pathology, and may last for several years according to individual resilience and brain reserve; (iii) clinically defined dementia phase of AD, in which cognitive and functional impairment is severe enough to surmount the dementia threshold; at this stage there is significant accumulation of neuritic plaques and neurofibrillary tangles in affected brain areas, bearing relationship with the magnitude of global impairment. New technologies based on structural and functional neuroimaging, and on the biochemical analysis of cerebrospinal fluid may depict correlates of intracerebral amyloidosis in individuals with mild, pre-dementia symptoms. These methods are commonly referred to as AD-related biomarkers, and the combination of clinical and biological information yields good diagnostic accuracy to identify individuals at high risk of AD. In other words, the characterization of pathogenic Aβ by means of biochemical analysis of biological fluids or by molecular neuroimaging are presented as diagnostic tools to help identify AD cases at the earliest stages of the disease process. The relevance of this early diagnosis of AD relies on the hypothesis that pharmacological interventions with disease-modifying compounds are more likely to produce clinically relevant benefits if started early enough in the continuum towards dementia. Therapies targeting the modification of amyloid-related cascades may be viewed as promising strategies to attenuate or even to prevent dementia. Therefore, the cumulative knowledge on the pathogenesis of AD derived from basic science models will hopefully be translated into clinical practice in the forthcoming years.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Brain Chemistry
* Humans
* Neocortex
* Peptide Fragments
* Phosphorylation
* Protein Processing, Post-Translational

|full-text-url=https://sci-hub.do/10.1007/978-94-007-5416-4_14
}}