Редактирование: ADAM10 (раздел)

==Publications==

{{medline-entry
|title=NKG2D Ligand Shedding in Response to Stress: Role of [[ADAM10]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32269567
|abstract=NKG2D is an activating receptor expressed by NK cells and some subsets of T cells and represents a major recognition receptor for detection and elimination of cancer cells. The ligands of NKG2D are stress-induced self-proteins that can be secreted as soluble molecules by protease-mediated cleavage. The release of NKG2D ligands in the extracellular milieu is considered a mode of finely controlling their surface expression levels and represents a relevant immune evasion mechanism employed by cancer cells to elude NKG2D-mediated immune surveillance. A disintegrin and metalloproteinase 10 ([[ADAM10]]), a catalytically active member of the ADAM family of proteases, is involved in the cleavage of some NKG2D ligands in various types of cancer cells either in steady state conditions and in response to an ample variety of stress stimuli. Appealing immunotherapeutic strategies devoted to promoting NK cell-mediated recognition and elimination of cancer cells are based on the upregulation of NK cell activating ligands. In particular, activation of DNA damage response (DDR) and the induction of cellular senescence by chemotherapeutic agents are associated with increased expression of NKG2D ligands on cancer cell surface. Herein, we will review advances on the protease-mediated cleavage of NKG2D ligands in response to chemotherapy-induced stress focusing on: (i) the role played by [[ADAM10]] in this process and (ii) the implications of NKG2D ligand shedding in the course of cancer therapy and in senescent cells.

|keywords=* ADAM10
* NKG2D
* NKG2D ligands
* cancer
* chemotherapy
* senescence
* shedding
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109295
}}
{{medline-entry
|title=Chronic Mild Stress Modified Epigenetic Mechanisms Leading to Accelerated Senescence and Impaired Cognitive Performance in Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32050516
|abstract=Cognitive and behavioural disturbances are a growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-κB pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 β (GSK-3β) inactivation, hyperphosphorylation of Tau and an increase in sAPPβ protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase [[ADAM10]] protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence.
|mesh-terms=* ADAM10 Protein
* Aging
* Amyloid Precursor Protein Secretases
* Animals
* Cognition
* Epigenesis, Genetic
* Female
* Glial Fibrillary Acidic Protein
* Glycogen Synthase Kinase 3 beta
* Mechanistic Target of Rapamycin Complex 1
* Membrane Proteins
* Mice
* MicroRNAs
* NF-kappa B
* Reactive Oxygen Species
* Signal Transduction
* Stress, Psychological
|keywords=* Alzheimer’s disease
* SAMP8
* SAMR1
* age-related cognitive decline
* autophagy
* cognition
* epigenetics
* inflammation
* oxidative stress
* senescence
* stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037343
}}
{{medline-entry
|title=Methyl-CpG Binding Protein 2 in Alzheimer Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31795606
|abstract=Despite decades of research on Alzheimer disease, understanding the complexity of the genetic and molecular interactions involved in its pathogenesis remains far from our grasp. Methyl-CpG Binding Protein 2 (MeCP2) is an important epigenetic regulator enriched in the brain, and recent findings have implicated MeCP2 as a crucial player in Alzheimer disease. Here, we provide comprehensive insights into the pathophysiological roles of MeCP2 in Alzheimer disease. In particular, we focus on how the alteration of MeCP2 expression can impact Alzheimer disease through risk genes, amyloid-β and tau pathology, cell death and neurodegeneration, and cellular senescence. We suggest that Alzheimer disease can be adversely affected by upregulated MeCP2-dependent repression of risk genes (MEF2C, [[ADAM10]], and PM20D1), increased tau accumulation, and neurodegeneration through neuronal cell death (excitotoxicity and apoptosis). In addition, we propose that the progression of Alzheimer disease could be caused by reduced MeCP2-mediated enhancement of astrocytic and microglial senescence and consequent glial SASP (senescence-associated secretory phenotype)-dependent neuroinflammation. We surmise that any imbalance in MeCP2 function would accelerate or cause Alzheimer disease pathogenesis, implying that MeCP2 may be a potential drug target for the treatment and prevention of Alzheimer disease.

|keywords=* Alzheimer disease
* MeCP2
* Neurodegeneration
* Neuroinflammation
* Risk genes
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905210
}}
{{medline-entry
|title=Removal of p75 Neurotrophin Receptor Expression from Cholinergic Basal Forebrain Neurons Reduces Amyloid-β Plaque Deposition and Cognitive Impairment in Aged APP/PS1 Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30374941
|abstract=The degeneration of cholinergic basal forebrain (cBF) neurons in Alzheimer's disease (AD) leads to the cognitive impairment associated with this condition. cBF neurons express the p75 neurotrophin receptor (p75 ), which mediates cell death, and the extracellular domain of p75  can bind to amyloid beta (Aβ) and promote its degradation. Here, we investigated the contribution of cBF neuronal p75  to the progression of AD by removing p75  from cholinergic neurons in the APP/PS1 familial AD mouse strain. Conditional loss of p75  slowed cognitive decline and reduced both Aβ accumulation into plaques and gliosis. Expression of the amyloid protein precursor and its cleavage enzymes [[ADAM10]] and [[BACE1]] were unchanged. There was also no upregulation of p75  in non-cholinergic cell types. This indicates that a direct interaction between cBF-expressed p75  and Aβ does not contribute significantly to the regulation of Aβ load. Rather, loss of p75  from cBF neurons, which results in increased cholinergic innervation of the cortex, appears to regulate alternative, more dominant, Aβ clearance mechanisms.
|mesh-terms=* Aging
* Alleles
* Amyloid beta-Peptides
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Basal Forebrain
* Cognitive Dysfunction
* Genotype
* Glial Fibrillary Acidic Protein
* Mice, Inbred C57BL
* Mice, Transgenic
* Neurons
* Presenilin-1
* Receptor, Nerve Growth Factor
|keywords=* Alzheimer’s disease
* Amyloid plaque
* Cholinergic basal forebrain
* Cognitive impairment
* Conditional knockout
* p75 extracellular domain
* p75 neurotrophin receptor
|full-text-url=https://sci-hub.do/10.1007/s12035-018-1404-2
}}
{{medline-entry
|title=11β-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29611102
|abstract=Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in [[ADAM10]] and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11β-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1β, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11β-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.
|mesh-terms=* 11-beta-Hydroxysteroid Dehydrogenase Type 1
* Alzheimer Disease
* Animals
* Anxiety
* Autophagy
* Beclin-1
* Biomarkers
* Cognition
* Disease Models, Animal
* Female
* Inflammation
* Memory
* Mice
* Mice, Neurologic Mutants
* Microtubule-Associated Proteins
* Models, Biological
* Nerve Degeneration
* Oxidative Stress
* Piperidones
* Pyridines
* TOR Serine-Threonine Kinases
|keywords=* APP
* Aging
* Behavior
* Cognition
* Hippocampus
* Inflammation
* Learning
* Neurodegeneration
* Oxidative stress
* Tau
|full-text-url=https://sci-hub.do/10.1007/s12035-018-1026-8
}}
{{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=microRNA 221 Targets [[ADAM10]] mRNA and is Downregulated in Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29036829
|abstract=[[ADAM10]] is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer's disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and [[ADAM10]] gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and [[ADAM10]] protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in [[ADAM10]] reduction and its inhibition in [[ADAM10]] increased. These findings show that miR-221 can be a new potential therapeutic target for increasing [[ADAM10]] levels in AD. In addition, these results can contribute to the better understanding of [[ADAM10]] post-transcriptional regulation.
|mesh-terms=* ADAM10 Protein
* Aged
* Aged, 80 and over
* Alzheimer Disease
* Cell Line, Tumor
* Cohort Studies
* Down-Regulation
* Female
* Humans
* Male
* MicroRNAs
* Middle Aged
* Neuroblastoma
* Psychiatric Status Rating Scales
* RNA, Messenger
* ROC Curve
* Transfection
|keywords=* ADAM10 protein
* Alzheimer’s disease
* aging
* biomarkers
* microRNAs
|full-text-url=https://sci-hub.do/10.3233/JAD-170592
}}
{{medline-entry
|title=Human Plasma Thioredoxin-80 Increases With Age and in ApoE  Mice Induces Inflammation, Angiogenesis, and Atherosclerosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28473446
|abstract=Thioredoxin (TRX)-1, a ubiquitous 12-kDa protein, exerts antioxidant and anti-inflammatory effects. In contrast, the truncated form, called TRX80, produced by macrophages induces upregulation of proinflammatory cytokines. TRX80 also promotes the differentiation of mouse peritoneal and human macrophages toward a proinflammatory M1 phenotype. TRX1 and TRX80 plasma levels were determined with a specific ELISA. A disintegrin and metalloproteinase domain-containing protein (ADAM)-10, ADAM-17, and ADAM-10 activities were measured with SensoLyte 520 [[ADAM10]] Activity Assay Kit, Fluorimetric, and InnoZyme TACE Activity Kit, respectively. Western immunoblots were performed with specific antibodies to ADAM-10 or ADAM-17. Angiogenesis study was evaluated in vitro with human microvascular endothelial cells-1 and in vivo with the Matrigel plug angiogenesis assay in mice. The expression of macrophage phenotype markers was investigated with real-time polymerase chain reaction. Phosphorylation of Akt, mechanistic target of rapamycin, and 70S6K was determined with specific antibodies. The effect of TRX80 on [[NLRP3]] inflammasome activity was evaluated by measuring the level of interleukin-1β and -18 in the supernatants of activated macrophages with ELISA. Hearts were used for lesion surface evaluation and immunohistochemical studies, and whole descending aorta were stained with Oil Red O. For transgenic mice generation, the human scavenger receptor (SR-A) promoter/enhancer was used to drive macrophage-specific expression of human TRX80 in mice. In this study, we observed a significant increase of plasma levels of TRX80 in old subjects compared with healthy young subjects. In parallel, an increase in expression and activity of ADAM-10 and ADAM-17 in old peripheral blood mononuclear cells compared with those of young subjects was observed. Furthermore, TRX80 was found to colocalize with tumor necrosis factor-α, a macrophage M1 marker, in human atherosclerotic plaque. In addition, TRX80 induced the expression of murine M1 macrophage markers through Akt2/mechanistic target of rapamycin-C1/70S6K pathway and activated the inflammasome [[NLRP3]], leading to the release of interleukin-1β and -18, potent atherogenic cytokines. Moreover, TRX80 exerts a powerful angiogenic effect in both in vitro and in vivo mouse studies. Finally, transgenic mice that overexpress human TRX80 specifically in macrophages of apoE  mice have a significant increase of aortic atherosclerotic lesions. TRX80 showed an age-dependent increase in human plasma. In mouse models, TRX80 was associated with a proinflammatory status and increased atherosclerosis.
|mesh-terms=* ADAM10 Protein
* ADAM17 Protein
* Adult
* Aged
* Aging
* Animals
* Apolipoproteins E
* Atherosclerosis
* Biomarkers
* Disease Models, Animal
* Down-Regulation
* Enzyme-Linked Immunosorbent Assay
* Female
* Humans
* Immunohistochemistry
* Inflammation
* Interleukin-18
* Interleukin-1beta
* Leukocytes, Mononuclear
* Lipopolysaccharides
* Macrophages
* Male
* Mechanistic Target of Rapamycin Complex 1
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Mice, Transgenic
* Microscopy, Confocal
* Multiprotein Complexes
* NLR Family, Pyrin Domain-Containing 3 Protein
* Neovascularization, Physiologic
* Peptide Fragments
* Proto-Oncogene Proteins c-akt
* Recombinant Proteins
* Sirolimus
* TOR Serine-Threonine Kinases
* Thioredoxins
|keywords=* atherosclerosis
* inflammasomes
* inflammation
* interleukin-1beta
* macrophages
* neovascularization
* thioredoxins
|full-text-url=https://sci-hub.do/10.1161/CIRCULATIONAHA.117.027612
}}
{{medline-entry
|title=Ionizing radiation reduces [[ADAM10]] expression in brain microvascular endothelial cells undergoing stress-induced senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28437250
|abstract=Cellular senescence is associated with aging and is considered a potential contributor to age-associated neurodegenerative disease. Exposure to ionizing radiation increases the risk of developing premature neurovascular degeneration and dementia but also induces premature senescence. As cells of the cerebrovascular endothelium are particularly susceptible to radiation and play an important role in brain homeostasis, we investigated radiation-induced senescence in brain microvascular endothelial cells (EC). Using biotinylation to label surface proteins, streptavidin enrichment and proteomic analysis, we analyzed the surface proteome of stress-induced senescent EC in culture. An array of both recognized and novel senescence-associated proteins were identified. Most notably, we identified and validated the novel radiation-stimulated down-regulation of the protease, a disintegrin and metalloprotease 10 ([[ADAM10]]). [[ADAM10]] is an important modulator of amyloid beta protein production, accumulation of which is central to the pathologies of Alzheimer's disease and cerebral amyloid angiopathy. Concurrently, we identified and validated increased surface expression of [[ADAM10]] proteolytic targets with roles in neural proliferation and survival, inflammation and immune activation (L1CAM, [[NEO1]], NEST, [[TLR2]], DDX58). [[ADAM10]] may be a key molecule linking radiation, senescence and endothelial dysfunction with increased risk of premature neurodegenerative diseases normally associated with aging.
|mesh-terms=* ADAM10 Protein
* Amyloid Precursor Protein Secretases
* Animals
* Autophagy
* Biotinylation
* Capillaries
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Down-Regulation
* Endothelial Cells
* Membrane Proteins
* Mice
* Neurons
* Proteomics
* Radiation, Ionizing
* Stress, Physiological
* alpha-Galactosidase
|keywords=* ADAM10
* biotinylation
* endothelial cells
* ionizing radiation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425125
}}
{{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=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=Effects of Sesaminol Feeding on Brain Aβ Accumulation in a Senescence-Accelerated Mouse-Prone 8.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27233432
|abstract=Alzheimer's disease (AD) is characterized by the progressive accumulation of extracellular β-amyloid (Aβ) aggregates. Recently, the senescence-accelerated mouse-prone 8 (SAMP8) model was highlighted as a useful model of age-related AD. Therefore, we used the SAMP8 mouse to investigate the preventive effects of sesame lignans on the onset of AD-like pathology. In preliminary in vitro studies, sesaminol showed the greatest inhibitory effect on Aβ oligomerization and fibril formation relative to sesamin, sesamolin, and sesaminol triglucoside. Hence, sesaminol was selected for further evaluation in vivo. In SAMP8 mice, feed-through sesaminol (0.05%, w/w, in standard chow) administered over a 16 week period reduced brain Aβ accumulation and decreased serum 8-hydroxydeoxyguanosine, an indicator of oxidative stress. Furthermore, sesaminol administration increased the gene and protein expression of [[ADAM10]], which is a protease centrally involved in the non-amyloidogenic processing of amyloid precursor protein. Taken together, these data suggest that long-term consumption of sesaminol may inhibit the accumulation of pathogenic Aβ in the brain. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Dioxoles
* Disease Models, Animal
* Furans
* Humans
* Male
* Mice
* Oxidative Stress
* Sesame Oil
* Sesamum
|keywords=* ADAM10
* Aβ
* SAMP8
* brain
* sesaminol
|full-text-url=https://sci-hub.do/10.1021/acs.jafc.6b01237
}}
{{medline-entry
|title=Behaviour and cognitive changes correlated with hippocampal neuroinflammaging and neuronal markers in female SAMP8, a model of accelerated senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27094468
|abstract=Senescence accelerated mice P8 (SAMP8) is a phenotypic model of age, characterized by deficits in memory and altered behaviour. Here, we determined the effect of age in SAMP8, and compared with the resistant strain, SAMR1, in behaviour and learning parameters linking these disturbances with oxidative stress environment. We found impairment in emotional behaviour with regard to fear and anxiety in young SAMP8 vs. age-mated SAMR1. Differences were attenuated with age. In contrast, learning capabilities are worse in SAMP8, both in young and aged animals, with regard to SAMR1. These waves in behaviour and cognition were correlated with an excess of oxidative stress (OS) in SAMP8 at younger ages that diminished with age. In this manner, we found changes in the hippocampal expression of [[ALDH2]], IL-6, [[HMOX1]], COX2, [[CXCL10]], iNOS, and MCP-1 with an altered amyloidogenic pathway by increasing the Amyloid beta precursor protein (APP) and [[BACE1]], and reduced [[ADAM10]] expression; in addition, astrogliosis and neuronal markers decreased. Moreover, Superoxide dismutase 1 (SOD1) and Nuclear factor-kappa beta (NF-kβ) expression and protein levels were higher in younger SAMP8 than in SAMR1. In conclusion, the accelerated senescence process present in SAMP8 can be linked with an initial deregulation in redox homeostasis, named neuroinflammaging, by inducing molecular changes that lead to neuroinflammation and the neurodegenerative process. These changes are reflected in the emotional and cognitive behaviour of SAMP8 that differs from that of SAMR1 and that highlighted the importance of earlier oxidative processes in the onset of neurodegeneration.
|mesh-terms=* Aging
* Animals
* Behavior, Animal
* Biomarkers
* Cognition
* Female
* Gene Expression
* Hippocampus
* Inflammation
* Male
* Memory
* Mice
* Models, Animal
* Oxidative Stress
|keywords=* Ageing
* Behaviour
* Cognition
* Inflammation
* Learning
* Neurodegeneration
* Oxidative stress
|full-text-url=https://sci-hub.do/10.1016/j.exger.2016.03.014
}}
{{medline-entry
|title=Epigenetic mechanisms underlying cognitive impairment and Alzheimer disease hallmarks in 5XFAD mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27013617
|abstract=5XFAD is an early-onset mouse transgenic model of Alzheimer disease (AD). Up to now there are no studies that focus on the epigenetic changes produced as a result of Aβ-42 accumulation and the possible involvement in the different expression of related AD-genes. Under several behavioral and cognition test, we found impairment in memory and psychoemotional changes in female 5XFAD mice in reference to wild type that worsens with age. Cognitive changes correlated with alterations on protein level analysis and gene expression of markers related with tau aberrant phosphorylation, amyloidogenic pathway (APP, BACE1), Oxidative Stress (iNOS, Aldh2) and inflammation (astrogliosis, [[TNF]]-α and IL-6); no changes were found in non-amyloidogenic pathway indicators such as [[ADAM10]]. Epigenetics changes as higher CpG methylation and transcriptional changes in DNA methyltransferases (DNMTs) family were found. Dnmt1 increases in younger 5XFAD and Dnmt3a and b high levels in the oldest transgenic mice. Similar pattern was found with histone methyltransferases such as Jarid1a andG9a. Histone deacetylase 2 (Hdac2) or Sirt6, both related with cognition and memory, presented a similar pattern. Taken together, these hallmarks presented by the 5XFAD model prompted its use in assessing different potential therapeutic interventions based on epigenetic targets after earlier amyloid deposition.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Cognition Disorders
* Cognitive Dysfunction
* Disease Models, Animal
* Epigenesis, Genetic
* Mice
* Mice, Transgenic
* Oxidative Stress
* Peptide Fragments
|keywords=* Alzheimer disease
* behavior
* cognition
* deacetylase
* methyltransferase
* neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925821
}}
{{medline-entry
|title=Increase of α-Secretase [[ADAM10]] in Platelets Along Cognitively Healthy Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26757187
|abstract=[[ADAM10]] is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (AβPP). Previous research with postmortem tissue has shown reduced expression and activity of [[ADAM10]] within the central nervous system (CNS) of Alzheimer's disease (AD) patients. Determination of cerebral [[ADAM10]] in living humans is hampered by its transmembrane property; only the physiological AβPP cleavage product generated by [[ADAM10]], sAβPPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that [[ADAM10]] is expressed in platelets and that platelet amount is decreased in AD patients. Just recently it has been shown that platelet [[ADAM10]] and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding [[ADAM10]] expression during normal aging. We investigated [[ADAM10]] amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22-85 years. Interestingly, we observed an age-dependent increase in [[ADAM10]] levels and activity in platelets. 
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Analysis of Variance
* Apolipoprotein E4
* Cognition
* Female
* Healthy Volunteers
* Humans
* Integrin beta3
* Male
* Membrane Proteins
* Middle Aged
* Neuropsychological Tests
* Young Adult
|keywords=* ADAM10
* fluorescence activity
* normal aging
* platelets
* resilience factor
|full-text-url=https://sci-hub.do/10.3233/JAD-150737
}}
{{medline-entry
|title=[[ADAM10]] gene expression in the blood cells of Alzheimer's disease patients and mild cognitive impairment subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26220620
|abstract=[[ADAM10]] is a potential biomarker for Alzheimer's disease (AD). [[ADAM10]] protein levels are reduced in platelets of AD patients. The aim was to verify the total blood and platelet [[ADAM10]] gene expression in AD patients and to compare with mild cognitive impairment (MCI) and healthy subjects. No significant differences in [[ADAM10]] gene expression were observed. Therefore, the decrease of [[ADAM10]] protein in platelets of AD patients is not caused by a reduction in [[ADAM10]] mRNA. Further studies must be performed to investigate other pathways in the down regulation of [[ADAM10]] protein. 
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* Aged
* Aged, 80 and over
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Biomarkers
* Blood Platelets
* Case-Control Studies
* Cognitive Dysfunction
* Female
* Gene Expression
* Humans
* Male
* Membrane Proteins
* Middle Aged
* Neuropsychological Tests
* RNA, Messenger
|keywords=* Aging
* biomarkers
* blood
* platelets
|full-text-url=https://sci-hub.do/10.3109/1354750X.2015.1062554
}}
{{medline-entry
|title=Serum Fragments of Tau for the Differential Diagnosis of Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26159200
|abstract=Differential diagnosis of AD is still a challenge due to overlapping features with other types of dementia. Biomarkers for the differential diagnosis of AD can improve the diagnostic value of the disease and ensure an appropriate treatment of patients. The aim of this study was to evaluate the potential of two neo-epitope fragments of Tau as serum biomarkers for differential diagnosis of AD. The neo-epitope fragments of Tau were assessed in a cross-sectional cohort of subjects with AD, MCI, other dementias or subjects with non-dementia related memory complaints. The two Tau neo-epitope fragments were an [[ADAM10]]-generated fragment (Tau-A) and a caspase-3-generated fragment (Tau-C). The serum levels of the fragments were measured by two competitive ELISAs detecting Tau-A and Tau-C, respectively. Tau-A and Tau-C were able to separate subjects with AD and MCI from those with other dementias (p<0.0042 and p<0.05), and Tau-A could also discriminate between AD and MCI patients and subjects with non-dementia related memory complaints (p<0.05). Tau-A showed a significantly greater discrimination between AD and MCI subjects and patients with other dementias when compared to CSF biomarkers t-Tau and p-Tau. The ability of Tau-A to differentiate between AD and MCI from other dementias was comparable with CSF Aβ1-42, t-Tau/Aβ1-42 and p-Tau/Aβ1-42. The separation between the diagnostic groups was significantly improved when the CSF biomarkers as well as age and BMI were used in combination with Tau-A (AUC=0.87, 95% CI: 0.75-0.94) (p<0.0001). In conclusion, this study shows that a neoepitope fragment of Tau detected in serum can provide guidance on the differential diagnosis of AD.
|mesh-terms=* Aged
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Area Under Curve
* Biomarkers
* Body Mass Index
* Cognitive Dysfunction
* Cross-Sectional Studies
* Diagnosis, Differential
* Enzyme-Linked Immunosorbent Assay
* Female
* Humans
* Logistic Models
* Male
* Middle Aged
* Peptide Fragments
* ROC Curve
* tau Proteins

|full-text-url=https://sci-hub.do/10.2174/1567205012666150710111211
}}
{{medline-entry
|title=Lack of [[ADAM10]] in endothelial cells affects osteoclasts at the chondro-osseus junction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24108673
|abstract=Mice lacking [[ADAM10]] in endothelial cells (Adam10ΔEC mice) have shorter femurs, tibiae, and humeri than controls, raising questions about how endothelial cells could control long bone growth. We performed a histopathological evaluation of the femur and tibia growth plates at different postnatal stages, and assessed the distribution of TRAP-positive osteoclasts and endothelial cells at the growth plate. The growth plates in Adam10ΔEC mice appeared normal at P7 and P14, but a thickened zone of hypertrophic chondrocytes and increased trabecular bone density were apparent by P21 and later. The number of TRAP  cells at the COJ was normal at P7 and P14, but was strongly reduced at P21 and later. Moreover, the density of endomucin-stained endothelial cells at the COJ was increased starting at P7. The defects in long bone growth in Adam10ΔEC mice could be caused by a lack of osteoclastogenesis at the COJ. Moreover, [[ADAM10]] appears to regulate endothelial cell organization in the developing bone vasculature, perhaps in a similar manner as in the developing retinal vascular tree, where [[ADAM10]] is thought to control Notch-dependent endothelial cell fate decisions. This study provides evidence for the regulation of osteoclast function by endothelial cells in vivo.
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* Acid Phosphatase
* Aging
* Amyloid Precursor Protein Secretases
* Animals
* Bone Development
* Bone and Bones
* Endothelial Cells
* Femur
* Growth Plate
* Isoenzymes
* Membrane Proteins
* Mice
* Osteoclasts
* Tartrate-Resistant Acid Phosphatase
* Tibia
|keywords=* ADAM10
* chondro-osseus junction
* endothelial cells
* growth plate
* osteoclasts
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978382
}}
{{medline-entry
|title=[The effect of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with alzheimer's disease].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23627094
|abstract=To explore the effects of PNS on the content and activity of alpha-secretase in the brains of SAMP8 mice with Alzheimer's disease. SAMP8 mice were randomly divided into four groups: PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. The high-dosage group and low-dosage group were treated with 200 and 100 mg/kg PNS respectively per day and the huperzine A group was treated with 0.3 mg/kg huperzine A per day, all by intragastric administration for 8 consecutive weeks. The same volume of double distilled water was given to the control group. The activity of a-secretase was assayed by direct immunofluorescent method(DIF). Western blot was used to detect the content of alpha-secretase including [[ADAM9]], [[ADAM10]] and [[ADAM17]] proteins. The Relative Fluorescence Units (RFU) of PNS high-dosage and low-dosage groups were higher than that of control group (P < 0.01). The results of western blot showed that the level of [[ADAM9]] protein expression in PNS high-dosage, low-dosage and huperzine A groups was significantly higher than that of control group (P < 0.05) while the levels of [[ADAM10]] protein expression in PNS high-dosage, low-dosage and huperzine A groups was significantly lower than that of control group (P < 0.05), while level of [[ADAM17]] of huperzine A group was higher than that of control group (P < 0.05). PNS can increase activity of alpha-secretase in the brain of SAMP8 mouse via increasing the level of [[ADAM9]] protein expression.
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* ADAM17 Protein
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Protein Precursor
* Animals
* Blotting, Western
* Brain
* Disease Models, Animal
* Female
* Gene Expression Regulation, Enzymologic
* Membrane Proteins
* Mice
* Panax notoginseng
* Random Allocation
* Saponins


}}
{{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=[[ADAM10]] as a biomarker for Alzheimer's disease: a study with Brazilian elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23306532
|abstract=Alzheimer's disease (AD) is the most common cause of dementia in people above age 65. Platelet studies with [[ADAM10]] have shown that its expression is reduced in AD patients. The aim of this research was to compare the platelet levels of [[ADAM10]] protein in two Brazilian elderly groups, considering the stages of the disease. The [[SDS]]-PAGE technique followed by Western blotting was used. Data were analyzed using comparison, correlation and association statistical methods. The results showed reduced platelet [[ADAM10]] levels in AD elderly compared to non-AD subjects. The disease progression intensified this reduction. [[ADAM10]] was the only statistically significant variable (p = 0.01) to increase the AD occurrence probability. The cutoff value of 0.4212 in the receiver operating characteristic curve captured sensitivity and specificity of 70 and 80.77%, respectively. Together with other clinical criteria, [[ADAM10]] seems to be a relevant biomarker tool for early and accurate AD diagnosis.
|mesh-terms=* ADAM Proteins
* ADAM10 Protein
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Biomarkers
* Blood Platelets
* Blotting, Western
* Brazil
* Data Interpretation, Statistical
* Diagnostic and Statistical Manual of Mental Disorders
* Educational Status
* Electrophoresis, Polyacrylamide Gel
* Female
* Humans
* Male
* Membrane Proteins
* Sex Characteristics

|full-text-url=https://sci-hub.do/10.1159/000345983
}}
{{medline-entry
|title=Sirtuins in cognitive ageing and Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22327552
|abstract=Sirtuins are a family of enzymes highly conserved in evolution and involved in mechanisms known to promote healthy ageing and longevity. This review aims to discuss recent advances in understanding the role of sirtuins, in particular mammalian [[SIRT1]], in promoting longevity and its potential molecular basis for neuroprotection against cognitive ageing and Alzheimer's disease pathology. Accumulative increase in oxidative stress during ageing has been shown to decrease [[SIRT1]] activity in catabolic tissue, possibly by direct inactivation by reactive oxygen. [[SIRT1]] overexpression prevents oxidative stress-induced apoptosis and increases resistance to oxidative stress through regulation of the FOXO family of forkhead transcription factors. In addition, resveratrol strongly stimulates [[SIRT1]] deacetylase activity in a dose-dependent manner by increasing its binding affinity to both the acetylated substrate and NAD( ). Recently, [[SIRT1]] has been shown to affect amyloid production through its influence over the [[ADAM10]] gene. Upregulation of [[SIRT1]] can also induce the Notch pathway and inhibit mTOR signalling. Recent studies have revealed some of the mechanisms and pathways that are associated with the neuroprotective effects of [[SIRT1]].
|mesh-terms=* Aging
* Alzheimer Disease
* Caloric Restriction
* Cognition
* Cognition Disorders
* Humans
* Longevity
* Neuroprotective Agents
* Oxidative Stress
* Sirtuin 1
* Sirtuins

|full-text-url=https://sci-hub.do/10.1097/YCO.0b013e32835112c1
}}
{{medline-entry
|title=The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/21349442
|abstract=Advances in gerontology have yielded crucial insights into the molecular and biochemical aspects of the ageing process. The sirtuin pathway, which is most notable for its association with the anti-ageing effects of calorie restriction, has received particular attention, and pharmacological or transgenic upregulation of the sirtuin pathway has shown promising results in laboratory models of ageing. Alzheimer's disease is a neurodegenerative disease that is imposing an increasing burden on society, and is the leading cause of senile dementia worldwide. The lack of therapies for Alzheimer's disease provides a strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a mechanism of action of the sirtuin pathway that might have therapeutic potential for Alzheimer's disease. [[SIRT1]], one of the seven mammalian proteins of the sirtuin family of NAD( )-dependent deacetylases, has recently been shown to attenuate amyloidogenic processing of amyloid-β protein precursor ([[APP]]) in cell culture studies in vitro and in transgenic mouse models of Alzheimer's disease. Mechanistically, [[SIRT1]] increases α-secretase production and activity through activation of the α-secretase gene [[ADAM10]]. Because α-secretase is the enzyme responsible for the non-amyloidogenic cleavage of [[APP]], upregulation of α-secretase shifts [[APP]] processing to reduce the pathological accumulation of the presumptive toxic Aβ species that results from β-secretase and γ-secretase activity. Interestingly, the spatial patterns of Aβ deposition in the brain might correlate with increased aerobic glycolysis in those regions. Because aerobic glycolysis depletes cellular levels of NAD( ) (through a decreased NAD( )/NADH ratio), it is possible that a corresponding downregulation of the NAD( )-dependent sirtuin pathway contributes to the amyloidogenic processing of [[APP]]. WHERE NEXT?: The specific inhibition of Aβ generation by [[SIRT1]] coupled with the potential link between aerobic glycolysis, NAD( ) depletion, and amyloidogenesis through the sirtuin pathway has translational implications. On the one hand, the possible underlying role of the sirtuin pathway in Alzheimer's disease onset and development might increase our understanding of this devastating condition. On the other hand, therapeutic upregulation of [[SIRT1]] might provide opportunities for the amelioration of Alzheimer's-disease-type neuropathology through inhibition of amyloidogenesis. Ultimately, further analysis into both aspects is necessary if any progress is to be made.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Humans
* Signal Transduction
* Sirtuin 1
* Sirtuins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163839
}}