Редактирование: CD68

Macrosialin precursor (Gp110) (CD68 antigen)

==Publications==

{{medline-entry
|title=Metformin alters peripheral blood mononuclear cells (PBMC) senescence biomarkers gene expression in type 2 diabetic patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33187870
|abstract=Although there is increasing evidence showing that cell senescence is increased in circulating PBMC in type 2 diabetes mellitus (T2DM), the data are contradictory. This study examined several senescence biomarkers, including [[LMNA]]/C transcript variants, p16 , p53, and p21 , in PBMC of T2DM patients and the effect of Metformin on these senescence markers. Blood samples were obtained from 30 lean, 30 obese, 20 newly diagnosed type 2 diabetes mellitus (T2DM), and 30 T2DM on Metformin. PBMC were isolated and mRNA expression of the senescence biomarkers were quantified by RT-qPCR. The effect of ectopic expression of [[LMNA]] and LMNC in human monocytic cells lines (THP-1 and U937) on several inflammatory mediators were also examined. [[LMNA]] expression was significantly higher in PBMC of obese and T2DM patients. LMNC expression was significantly inhibited in T2DM patients. [[LMNA]]Δ10 and Progerin mRNA expression was not detected in PBMC of all groups. Expression of p16 , p21  and p53 were inhibited significantly in T2DM. Metformin treatment reverted [[LMNA]], LMNC, and p53 expression levels to normal levels. Upregulation of [[LMNA]] in monocytic THP-1 and U937 cell lines induced [[CD68]], TNFα, [[CCL2]], IL-6 and [[NOS2]]. These data support the notion that [[LMNA]] may mediate senescence in PBMCs of T2DM by upregulating inflammatory pathways. Metformin may exert its anti-inflammatory property by modulation of senescence mediator [[LMNA]].

|keywords=* Inflammation and cellular senescence
* Insulin resistance
* LMNA/C transcript variants
* Mononuclear cells
* Type 2 diabetes mellitus
|full-text-url=https://sci-hub.do/10.1016/j.jdiacomp.2020.107758
}}
{{medline-entry
|title=Microglial changes in the early aging stage in a healthy retina and an experimental glaucoma model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32958210
|abstract=Glaucoma is an age-related neurodegenerative disease that begins at the onset of aging. In this disease, there is an involvement of the immune system and therefore of the microglia. The purpose of this study is to evaluate the microglial activation using a mouse model of ocular hypertension (OHT) at the onset of aging. For this purpose, we used both naive and ocular hypertensives of 15-month-old mice (early stage of aging). In the latter, we analyzed the OHT eyes and the eyes contralateral to them to compare them with their aged controls. In the eyes of aged naive, aged OHT and aged contralateral eyes, microglial changes were observed compared to the young mice, including: (i) aged naive vs young naive: An increased soma size and vertical processes; (ii) aged OHT eyes vs young OHT eyes: A decrease in the area of the retina occupied by Iba-1 cells and in vertical processes; and (iii) aged contralateral vs young contralateral: A decrease in the soma size and arbor area and an increase in the number of microglia in the outer segment layer. Aged OHT eyes and the eyes contralateral to them showed an up-regulation of the [[CD68]] expression in the branched microglia and a down-regulation in the MHCII and [[P2RY12]] expression with respect to the eyes of young OHT mice. Conclusion: in the early phase of aging, morphological microglial changes along with changes in the expression of MHCII, [[CD68]] and [[P2RY12]], in both naive and OHT mice. These changes appear in aged OHT eyes and the eyes contralateral to them eyes.

|keywords=* Aging
* CD68
* Glaucoma
* Iba-1
* Inflammation
* MHCII
* Microglia
* Mouse
* Ocular hypertension
* P2RY12
* Retina
|full-text-url=https://sci-hub.do/10.1016/bs.pbr.2020.05.024
}}
{{medline-entry
|title=Gliosis Precedes Amyloid-β Deposition and Pathological Tau Accumulation in the Neuronal Cell Cycle Re-Entry Mouse Model of Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32904753
|abstract=The presence of cell cycle markers in postmortem Alzheimer's disease (AD) brains suggest a potential role of cell cycle activation in AD. It was shown that cell cycle activation in postmitotic neurons in mice produces Aβ and tau pathologies from endogenous mouse proteins in the absence of AβPP or tau mutations. In this study, we examined the microglial and astrocytic responses in these mice since neuroinflammation is another key pathological feature in AD. Our neuronal cell cycle re-entry (NCCR) mouse model are bitransgenic mice heterozygous for both Camk2a-tTA and TRE-SV40T. Using this tet-off system, we triggered NCCR in our animals via neuronal expression of SV40T starting at 1 month of age. TRE-SV40T Tg mice were used as SV40T transgene controls. The animals were examined at following time points: 2, 3, 4, 6, and 12 months of age. The microglia and astrocyte responses in our mice were determined by image analysis and stereology on brain sections immunofluorescently labeled using the following antibodies: Iba1, CD45, [[CD68]], MHCII, and [[GFAP]]. Cellular senescent marker p16 was also used in this study. Our NCCR mice demonstrate early and persistent activation of microglia and astrocytes. Additionally, proinflammatory and senescent microglia phenotype and brain leukocyte infiltration is present at 12 months of age. In the absence of FAD gene mutations, our NCCR mice simultaneously display many of the pathological changes associated with AD, such as ectopic neuronal cell cycle re-entry, Aβ and tau pathologies, neuroinflammation, and neurodegeneration. These animals represent a promising alternative AD mouse model.

|keywords=* Alzheimer’s disease
* amyloid-β
* cell cycle
* leukocyte infiltration
* mouse model
* neuroinflammation
* senescence
* sporadic AD
* tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458550
}}
{{medline-entry
|title=Insulin activates microglia and increases COX-2/IL-1β expression in young but not in aged hippocampus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32422127
|abstract=Brain insulin resistance and neuroinflammation are known to increase with age. Insulin exerts metabolic roles on neurons and astrocytes, but its effects on microglia is unclear. In this study we investigated whether insulin affected microglia in the hippocampus of young and aged rats. We injected intracerebroventricular (i.c.v.) insulin (20 mU) or vehicle for five days and evaluated microglial inflammatory markers in the hippocampus of young (3 months) Wistar rats. Increased microglial activation (Iba-1 [[CD68]] cells) and COX-2/IL-1β levels in the hippocampus were found. Since the aged brain is an experimental model for brain insulin resistance and chronic neuroinflammation we submitted aged rats (22 months) to i.c.v. insulin/vehicle administration and found no significant increase in Iba-1 [[CD68]]  microglia or COX-2/IL-1β levels. To further investigate whether insulin triggered transient or persistent proinflammatory responses, young rats were evaluated eight-days after the last insulin injection. Microglia were persistently activated, and COX-2 levels remained elevated in the hippocampus, which paralleled increased spatial memory performance in the Morris Water Maze behavioral task. To determine if microglia were directly responsive to insulin, primary microglia were challenged with insulin and increased Akt Ser473 phosphorylation, a protein activated by the insulin receptor, was detected. These data suggest that microglia in the hippocampus integrate insulin signaling and neuroinflammatory responses and that this signal is disrupted during chronic inflammation. In our concept, the disruption between microglia activation by insulin signaling is a new pathological mechanism behind insulin resistance in the aging brain.

|keywords=* Aging
* Hippocampus
* Insulin
* Memory
* Microglia
* Neuroinflammation
|full-text-url=https://sci-hub.do/10.1016/j.brainres.2020.146884
}}
{{medline-entry
|title=Epigenetic modulation of macrophage polarization prevents lumbar disc degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32310825
|abstract=Inflammation plays an essential role in the development of lumbar disc degeneration (LDD), although the exact effects of macrophage subtypes on LDD remain unclear. Based on previous studies, we hypothesized that M2-polarization of local macrophages and simultaneous suppression of their production of fibrotic transforming growth factor beta 1 (TGFβ1) could inhibit progression of LDD. Thus, we applied an orthotopic injection of adeno-associated virus (AAV) carrying shRNA for DNA Methyltransferase 1 (DNMT1) and/or shRNA for TGFβ1 under a macrophage-specific [[CD68]] promoter to specifically target local macrophages in a mouse model for LDD. We found that shDNMT1 significantly reduced levels of the pro-inflammatory cytokines TNFα, IL-1β and IL-6, significantly increased levels of the anti-inflammatory cytokines IL-4 and IL-10, significantly increased M2 macrophage polarization, significantly reduced cell apoptosis in the disc degeneration zone and significantly reduced LDD-associated pain. The anti-apoptotic and anti-pain effects were further strengthened by co-application of shTGFβ1. Together, these data suggest that M2 polarization of macrophages induced by both epigenetic modulation and suppressed production and release of TGFβ1 from polarized M2 macrophages, may have a demonstrable therapeutic effect on LDD.

|keywords=* DNA methyltransferase 1 (DNMT1)
* aging
* lumbar disc degeneration (LDD)
* macrophage polarization
* transforming growth factor beta 1 (TGFβ1)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202517
}}
{{medline-entry
|title=Cellular senescence in recurrent tonsillitis and tonsillar hypertrophy in children.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32200310
|abstract=To observe the difference in cellular senescence patterns between recurrent tonsillitis and tonsillar hypertrophy. Forty-three patients diagnosed with recurrent tonsillitis or tonsillar hypertrophy, based on medical history and symptoms, underwent tonsillectomy. The specimens were collected and examined using senescence β-galactosidase staining for cellular senescence. Macrophages were detected by immunochemistry. Cellular senescence was found in both recurrent tonsillitis and tonsillar hypertrophy groups. The comparison of cellular senescence in microcompartments of tonsil tissue (germinal centre, mantle zone, subepithelial and intraepithelial) revealed a significant increase of senescent cells in germinal centres in tonsillar hypertrophy compared with that in tonsillar hypertrophy. The majority of senescent cells in both groups were [[CD68]]-positive. Different cellular senescence patterns were found between the two studied paediatric tonsillar diseases. Macrophage senescence may play a role in the pathogenesis of these diseases.
|mesh-terms=* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Cellular Senescence
* Child
* Germinal Center
* Humans
* Hypertrophy
* Macrophages
* Palatine Tonsil
* Recurrence
* Tonsillectomy
* Tonsillitis
|keywords=* Cellular senescence
* Recurrent tonsillitis
* Tonsillar hypertrophy
|full-text-url=https://sci-hub.do/10.1016/j.ijporl.2020.110004
}}
{{medline-entry
|title=[[NDRG2]] Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31947996
|abstract=Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer's disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 ([[NDRG2]]) in the ageing brain, investigate the relationship between [[NDRG2]] and a panel of astrocyte markers, and relate [[NDRG2]] expression to pathology. [[NDRG2]] specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of [[NDRG2]] did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). [[NDRG2]] showed a relationship to AT8  neurofibrillary tangles ([i]p[/i] = 0.001) and [[CD68]]  microglia ([i]p[/i] = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest [[NDRG2]] may be a potential target to modulate this response.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Astrocytes
* Brain
* DNA Damage
* Excitatory Amino Acid Transporter 2
* Gene Expression Regulation
* Glial Fibrillary Acidic Protein
* Glutamate-Ammonia Ligase
* Humans
* Microglia
* Neurofibrillary Tangles
* Tumor Suppressor Proteins
* tau Proteins
|keywords=* N-myc downstream regulated gene 2 (NDRG2)
* ageing brain
* astrocyte
* neurofibrillary tangles
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982267
}}
{{medline-entry
|title=Patterns of Expression of Purinergic Receptor [[P2RY12]], a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer's Disease Brains.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31968618
|abstract=Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer's disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor [[P2RY12]]-positive microglia, a marker previously defined as identifying homeostatic or non-activated microglia. We examined the expression of [[P2RY12]] by dual-color light and fluorescence immunohistochemistry using sections of middle temporal gyrus from AD, high plaque and low plaque non-demented cases in relation to amyloid beta (Aβ) plaques and phosphorylated tau, markers of pathology, and HLA-DR, IBA-1, [[CD68]], and progranulin, microglial phenotype markers. In low plaque cases, [[P2RY12]]-positive microglia mostly had non-activated morphologies, while the morphologies of [[P2RY12]]-positive microglia in AD brains were highly variable, suggesting its expression could encompass a wider range of phenotypes than originally hypothesized. [[P2RY12]] expression by microglia differed depending on the types of plaques or tangles they were associated with. Areas of inflammation characterized by lack of [[P2RY12]]-positive microglia around mature plaques could be observed, but many diffuse plaques showed colocalization with [[P2RY12]]-positive microglia. Based on these results, [[P2RY12]] expression by microglia should not be considered solely a marker of resting microglia as [[P2RY12]] immunoreactivity was identifying microglia positive for [[CD68]], progranulin and to a limited extent HLA-DR, markers of activation.
|mesh-terms=* Aging
* Alzheimer Disease
* Biomarkers
* Brain
* Humans
* Immunohistochemistry
* Inflammation
* Macrophages
* Microglia
* Phenotype
* Plaque, Amyloid
* Receptors, Purinergic P2Y2
|keywords=* Alzheimer’s disease
* activation phenotypes
* amyloid
* immunohistochemistry
* microglia
* neuroinflammation
* temporal cortex
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014248
}}
{{medline-entry
|title=Ginsenoside Rg1 supplementation clears senescence-associated β-galactosidase in exercising human skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31695564
|abstract=Ginsenoside Rg1 has been shown to clear senescence-associated beta-galactosidase (SA-β-gal) in cultured cells. It remains unknown whether Rg1 can influence SA-β-gal in exercising human skeletal muscle. To examine SA-β-gal change, 12 young men (age 21 ± 0.2 years) were enrolled in a randomized double-blind placebo controlled crossover study, under two occasions: placebo (PLA) and Rg1 (5 mg) supplementations 1 h prior to a high-intensity cycling (70% VO ). Muscle samples were collected by multiple biopsies before and after cycling exercise (0 h and 3 h). To avoid potential effect of muscle biopsy on performance assessment, cycling time to exhaustion test (80% VO ) was conducted on another 12 participants (age 23 ± 0.5 years) with the same experimental design. No changes of SA-β-gal were observed after cycling in the PLA trial. On the contrary, nine of the 12 participants showed complete elimination of SA-β-gal in exercised muscle after cycling in the Rg1 trial ([i]p[/i] < 0.05). Increases in apoptotic DNA fragmentation (PLA:  87% vs. Rg1:  133%, [i]p[/i] < 0.05) and [[CD68]]  (PLA:  78% vs. Rg1:  121%, [i]p[/i] = 0.17) occurred immediately after cycling in both trials. During the 3-h recovery, reverses in apoptotic nuclei content (PLA:  5% vs. Rg1: -32%, [i]p[/i] < 0.01) and increases in inducible nitrate oxide synthase and interleukin 6 mRNA levels of exercised muscle were observed only in the Rg1 trial ([i]p[/i] < 0.01). Rg1 supplementation effectively eliminates senescent cells in exercising human skeletal muscle and improves high-intensity endurance performance.

|keywords=* Cellular senescence
* Endurance
* Ergogenic aid
* Inflammation
* Macrophage
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823780
}}
{{medline-entry
|title=Compromised Bone Healing in Aged Rats Is Associated With Impaired M2 Macrophage Function.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31681320
|abstract=Fracture repair is initiated by a multitude of immune cells and induction of an inflammatory cascade. Alterations in the early healing response due to an aged adaptive immune system leads to impaired bone repair, delayed healing or even formation of non-union. However, immuno-senescence is not limited to the adaptive immunity, but is also described for macrophages, main effector cells from the innate immune system. Beside regulation of pro- and anti-inflammatory signaling, macrophages contribute to angiogenesis and granulation tissue maturation. Thus, it seems likely that an altered macrophage function due to aging may affect bone repair at various stages and contribute to age related deficiencies in bone regeneration. To prove this hypothesis, we analyzed the expression of macrophage markers and angiogenic factors in the early bone hematoma derived from young and aged osteotomized Spraque Dawley rats. We detected an overall reduced expression of the monocyte/pan-macrophage markers [[CD14]] and [[CD68]] in aged rats. Furthermore, the analysis revealed an impaired expression of anti-inflammatory M2 macrophage markers in hematoma from aged animals that was connected to a diminished revascularization of the bone callus. To verify that the age related disturbed bone regeneration was due to a compromised macrophage function, [[CD14]]  macrophage precursors were transplanted locally into the osteotomy gap of aged rats. Transplantation rescued bone regeneration partially after 6 weeks, demonstrated by a significantly induced deposition of new bone tissue, reduced fibrosis and significantly improved callus vascularization.
|mesh-terms=* Age Factors
* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Biomarkers
* Bone Regeneration
* Bone and Bones
* Female
* Fractures, Bone
* Gene Expression
* Lipopolysaccharide Receptors
* Macrophages
* Osteotomy
* Rats, Sprague-Dawley
* Wound Healing
|keywords=* CD14  cells
* aging
* angiogenesis
* bone regeneration
* compromised healing
* macrophage
* monocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813416
}}
{{medline-entry
|title=Young and elderly oral squamous cell carcinoma patients present similar angiogenic profile and predominance of M2 macrophages: Comparative immunohistochemical study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31497915
|abstract=M2 macrophages are often detected in oral squamous cell carcinoma (OSCC), which, influenced by hypoxic conditions, appear to have high angiogenesis-inducing capacity. However, the effects of immunosenescence on tumor-associated macrophages (TAMs) and angiogenesis in OSCC are unknown. Fifty-seven OSCCs were divided into 3 groups (I: <40 years [n = 17]; II: 40-65 years [n = 20]; III: >65 years [n = 20]). Immunohistochemistry for [[CD68]] and [[CD163]] (TAMs), and [[CD34]] and D2-40 for microvessel density ([[MVD]]), microvessel area (MVA), and total vascular area (TVA) were performed. All groups showed similar clinicopathological and immunohistochemical findings. Similar [[CD68]] and [[CD163]] expression, confirmed a M2 phenotype. [[MVD]], MVA, and TVA were similar, however, with significant predominance of blood vessels. No significant correlation between macrophage and angiogenic markers was observed. A similar TAM and angiogenesis profile suggests the participation of other mechanisms, instead immunosenescence, in young and elderly OSCC patients.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Carcinoma, Squamous Cell
* Female
* Humans
* Immunohistochemistry
* Immunosenescence
* Macrophages
* Male
* Middle Aged
* Mouth Neoplasms
* Neovascularization, Pathologic
* Receptors, Cell Surface
* Tumor Microenvironment
|keywords=* M1 and M2 macrophages
* angiogenesis
* immunohistochemistry
* immunosenescence
* oral squamous cell carcinoma
|full-text-url=https://sci-hub.do/10.1002/hed.25954
}}
{{medline-entry
|title=Histopathological, immunohistochemical, and molecular studies for determination of wound age and vitality in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31448552
|abstract=In forensic medicine, it is vital to verify with the best attainable accuracy once injuries occurred during vital or post-mortem conditions. An immunohistochemical study was carried out to examine the time-dependent expression of macrophage-specific gene [[CD68]] (cluster of differentiation 68), alpha-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) in different skin wound timings (0, 1, 3, 5, 7, and 14 days) in rats. Histopathological studies were performed to assess the wound age and vitality. Eighteen male albino Wister rats (weighing 170-200 g) were used for wound induction. Rats (n = 3) were euthanised at 0, 1, 3, 5, 7, and 14 days from the starting point of wound induction. Histopathological examination showed that the epidermal re-epithelialisation was completed 14 days after skin incision. The inflammatory phase was recorded during the first 3 days of healing and reached the maximum levels at 5 days, then declined after 7 days, and completely removed at 14 days. The beginning of the proliferative phase was dated to day 3 and the peak at days 5 and 7. The initiation of the granulation tissue formation and remodelling phase of the healing process was observed 5 days after wounding. By immunohistochemical staining, negative VEGF gene expressions at early stages (0-3 days) were observed, as well as neither [[CD68]]  macrophages nor α-SMA  myofibroblast cells were detected. By increasing the wound ages (5-7 days), granulation tissue and angiogenesis were observed, with the migration of macrophages and fibroblast, which expressed VEGF, [[CD68]], and α-SMA positive reaction. Time-dependent expression of the above markers suggested that they would be useful indicators for the determination of wound age. Both VEGF and transforming growth factor-beta 1 (TGFb1) mRNA levels were determined in different skin wound ages. The transcription of TGFb1 and VEGF increased shortly after wounding, until post-wounding day 7. It then declined constantly, reaching minimal values on day 14.
|mesh-terms=* Actins
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Cell Movement
* Fibroblasts
* Granulation Tissue
* Immunohistochemistry
* Macrophages
* Models, Animal
* Neovascularization, Physiologic
* RNA, Messenger
* Rats, Wistar
* Re-Epithelialization
* Skin
* Time Factors
* Transforming Growth Factor beta1
* Vascular Endothelial Growth Factor A
* Wound Healing
* Wounds and Injuries
|keywords=* TGFb1
* VEGF
* gene expression
* immunohistochemistry
* wound aging
|full-text-url=https://sci-hub.do/10.1111/iwj.13206
}}
{{medline-entry
|title=Metabotropic glutamate receptor 5 ablation accelerates age-related neurodegeneration and neuroinflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30930274
|abstract=The growing elderly population world widely prompts the need for studies regarding aged brain and its susceptibility to neurodegenerative diseases. It has been shown that aged brain exhibits several alterations, including neuroinflammation, which prone this organ to neurodegenerative processes. Metabotropic glutamate receptor 5 (mGlu  receptor) has a role in neuronal cell loss and inflammation. Although the relevance of mGlu  receptor in different diseases has been investigated, its involvement in normal brain aging remains unclear. In the present study, we used the mGlu  receptor knockout (mGluR5 ) mice, a model of Huntington's Disease (BACHD), and the double mutant mice (mGluR5 /BACHD), at the ages of 2, 6 and 12 months, to investigate whether mGlu  receptor has a role in brain aging. We demonstrated that mGluR5  mice exhibit diminished number of neurons at 12 months of age in the cortex and striatum, similarly to what was observed in the case of BACHD and mGluR5 /BACHD mice. In addition, ablation of mGlu  receptor increased the number of astrocytes and microglia in BACHD and wild type (WT) mice in an age-dependent manner in the cortical region, but not in the striatum. Interestingly, 12-month-old mGluR5  mice induced microglia activation, evidenced by increased [[CD68]] expression and diminished number of microglia ramifications in skeleton analyses. Importantly, the presence of mutant huntingtin and the absence of mGlu  receptor promoted decreased levels of fractalkine expression in aged mice, which could account for the decreased levels of microglia activation in these mice. Together, our data provide evidence that mGlu  receptor plays a role in brain aging by modulating different cell types in the central nervous system (CNS).
|mesh-terms=* Aging
* Animals
* Brain
* Huntington Disease
* Inflammation
* Inflammation Mediators
* Mice
* Mice, 129 Strain
* Mice, Knockout
* Mice, Transgenic
* Microglia
* Neurodegenerative Diseases
* Receptor, Metabotropic Glutamate 5
|keywords=* Aging
* Huntington's disease
* Neurodegeneration
* Neuroinflammation
* mGlu(5) receptor
|full-text-url=https://sci-hub.do/10.1016/j.neuint.2019.03.020
}}
{{medline-entry
|title=Iba-1-/[[CD68]]  microglia are a prominent feature of age-associated deep subcortical white matter lesions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30682074
|abstract=Deep subcortical lesions (DSCL) of the brain, are present in ~60% of the ageing population, and are linked to cognitive decline and depression. DSCL are associated with demyelination, blood brain barrier (BBB) dysfunction, and microgliosis. Microglia are the main immune cell of the brain. Under physiological conditions microglia have a ramified morphology, and react to pathology with a change to a more rounded morphology as well as showing protein expression alterations. This study builds on previous characterisations of DSCL and radiologically 'normal-appearing' white matter (NAWM) by performing a detailed characterisation of a range of microglial markers in addition to markers of vascular integrity. The Cognitive Function and Ageing Study (CFAS) provided control white matter (WM), NAWM and DSCL human post mortem tissue for immunohistochemistry using microglial markers (Iba-1, [[CD68]] and MHCII), a vascular basement membrane marker (collagen IV) and markers of BBB integrity (fibrinogen and aquaporin 4). The immunoreactive profile of [[CD68]] increased in a stepwise manner from control WM to NAWM to DSCL. This correlated with a shift from small, ramified cells, to larger, more rounded microglia. While there was greater Iba-1 immunoreactivity in NAWM compared to controls, in DSCL, Iba-1 levels were reduced to control levels. A prominent feature of these DSCL was a population of Iba-1-/[[CD68]]  microglia. There were increases in collagen IV, but no change in BBB integrity. Overall the study shows significant differences in the immunoreactive profile of microglial markers. Whether this is a cause or effect of lesion development remains to be elucidated. Identifying microglia subpopulations based on their morphology and molecular markers may ultimately help decipher their function and role in neurodegeneration. Furthermore, this study demonstrates that Iba-1 is not a pan-microglial marker, and that a combination of several microglial markers is required to fully characterise the microglial phenotype.
|mesh-terms=* Aging
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Biomarkers
* Blood-Brain Barrier
* Calcium-Binding Proteins
* Cell Shape
* Cognitive Dysfunction
* DNA-Binding Proteins
* Histocompatibility Antigens Class II
* Humans
* Immunohistochemistry
* Microfilament Proteins
* Microglia
* Myelin Sheath
* White Matter

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347230
}}
{{medline-entry
|title=Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30477578
|abstract=Microglia are the resident innate immune cells of the central nervous system. Limited turnover throughout the lifespan leaves microglia susceptible to age-associated dysfunction. Indeed, we and others have reported microglia develop a pro-inflammatory or "primed" profile with age, characterized by increased expression of inflammatory mediators (e.g., MHC-II, [[CD68]], IL-1β). Moreover, immune challenge with lipopolysaccharide (LPS) causes an exaggerated and prolonged neuroinflammatory response mediated by primed microglia in the aged brain. Recent studies show colony-stimulating factor 1 receptor ([[CSF1R]]) antagonism results in rapid depletion of microglia without significant complications. Therefore, we hypothesized that [[CSF1R]] antagonist-mediated depletion of microglia in the aged brain would result in repopulation with new and unprimed microglia. Here we provide novel evidence that microglia in the brain of adult (6-8 weeks old) and aged (16-18 months old) BALB/c mice were depleted following 3-week oral PLX5622 administration. When [[CSF1R]] antagonism was stopped, microglia repopulated equally in the adult and aged brain. Microglial depletion and repopulation reversed age-associated increases in microglial [[CD68]]  lysosome enlargement and lipofuscin accumulation. Microglia-specific RNA sequencing revealed 511 differentially expressed genes with age. Of these, 117 genes were reversed by microglial repopulation (e.g., Apoe, Tgfb2, Socs3). Nevertheless, LPS challenge still induced an exaggerated microglial inflammatory response in the aged brain compared to adults. RNA sequencing of whole-brain tissue revealed an age-induced inflammatory signature, including reactive astrocytes, that was not restored by microglial depletion and repopulation. Furthermore, the microenvironment of the aged brain produced soluble factors that influenced developing microglia ex vivo and induced a profile primed to LPS challenge. Thus, the aged brain microenvironment promotes microglial priming despite repopulation of new microglia. Collectively, aged microglia proliferate and repopulate the brain, but these new cells still adopt a pro-inflammatory profile in the aged brain.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Brain
* CD11b Antigen
* Cell Proliferation
* Gene Expression Regulation
* Glial Fibrillary Acidic Protein
* Humans
* Leukocyte Common Antigens
* Lipofuscin
* Lipopolysaccharides
* Male
* Mice
* Mice, Inbred BALB C
* Microglia
* Organic Chemicals
* RNA, Messenger
* Social Behavior
|keywords=* Age
* CSF1R antagonist
* Lipopolysaccharide
* Microglia
* Priming
* RNA-Seq
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260864
}}
{{medline-entry
|title=Partial reduction of microglia does not affect tau pathology in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30413160
|abstract=Activation of inflammation pathways in the brain occurs in Alzheimer's disease and may contribute to the accumulation and spread of pathological proteins including tau. The goal of this study was to identify how changes in microglia, a key inflammatory cell type, may contribute to tau protein accumulation and pathology-associated changes in immune and non-immune cell processes such as neuronal degeneration, astrocyte physiology, cytokine expression, and blood vessel morphology. We used PLX3397 (290 mg/kg), a colony-stimulating factor receptor 1 (CSF1R) inhibitor, to reduce the number of microglia in the brains of a tau-overexpressing mouse model. Mice were fed PLX3397 in chow or a control diet for 3 months beginning at 12 months of age and then were subsequently analyzed for changes in blood vessel morphology by in vivo two-photon microscopy and tissues were collected for biochemistry and histology. PLX3397 reduced microglial numbers by 30% regardless of genotype compared to control diet-treated mice. No change in tau burden, cortical atrophy, blood vessels, or astrocyte activation was detected. All Tg4510 mice were observed to have an increased in "disease-associated" microglial gene expression, but PLX3397 treatment did not reduce expression of these genes. Surprisingly, PLX3397 treatment resulted in upregulation of [[CD68]] and Tgf1β. Manipulating microglial activity may not be an effective strategy to combat tau pathological lesions. Higher doses of PLX3397 may be required or earlier intervention in the disease course. Overall, this indicates a need for a better understanding of specific microglial changes and their relation to the disease process.
|mesh-terms=* Aging
* Aminopyridines
* Animals
* Blood Vessels
* Calcium-Binding Proteins
* Calcium-Calmodulin-Dependent Protein Kinase Type 2
* Cytokines
* Disease Models, Animal
* Gene Expression Regulation
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microfilament Proteins
* Microglia
* Mutation
* Pyrroles
* RNA, Messenger
* Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
* Tauopathies
* tau Proteins
|keywords=* Alzheimer’s disease
* Microglia
* Tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230271
}}
{{medline-entry
|title=Effects of pepsin and pepstatin on reflux tonsil hypertrophy in vitro.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30408092
|abstract=There is evidence that pepsin can aggravate tonsil hypertrophy. Pepstatin is a potent inhibitor of pepsin activity and could protect patients against reflux tonsil hypertrophy by inhibiting pepsin. We examined the effects of pepstatin on the development of tonsil hypertrophy to investigate pepsin's role in the pathogenesis of tonsil lesions. We investigated whether pepstatin suppresses pepsin-mediated lymphocyte proliferation in tonsil hypertrophy. Forty-nine children with tonsil hypertrophy and twenty-two adults with tonsillitis were recruited to the study prior to surgery. Tonsil tissue from each patient was harvested and assessed for changes in the number of lymphocytes and macrophages in the presence of pepsin and pepstatin. We found that the proportions of [[CD4]]- and [[CD14]]-positive cells were significantly lower (p < 0.05), but that the proportions of [[CD19]]- and [[CD68]]-positive cells were significantly higher (p < 0.05), in children than in adults. There were significantly more [[CD4]]-positive cells after pepsin treatment, but these numbers were reduced by pepstatin. The levels of both interleukin-2 (IL-2) and interferon gamma (IFN-γ) increased significantly in response to pepsin, but were reduced when pepsin was inhibited by pepstatin. The level of IL-10 is reduced in pepsin-treated [[CD4]] cells and the level is restored by pepstatin. IL-2 blocking reduced the increased [[CD4]] cell number by pepsin. But, an additive or a synergic effect is not founded in combined with IL-2 blocking and pepstatin. Pepsin-positive cells did not co-localize with CD20 and [[CD4]]5 cells, but they were found surrounding CD20- and [[CD4]]5-positive hypertrophic tonsil cells. Pepsin-positive cells co-localized with [[CD68]]-positive cells. It is probable that pepsin from extraesophageal reflux aggravates tonsil hypertrophy and pepstatin exerts a protective effect by inhibiting pepsin activity.
|mesh-terms=* Adolescent
* Adult
* Aging
* Child
* Child, Preschool
* Female
* Humans
* Hypertrophy
* In Vitro Techniques
* Interferon-gamma
* Interleukin-10
* Interleukin-2
* Lymphocytes
* Macrophages
* Male
* Palatine Tonsil
* Pepsin A
* Pepstatins
* Pharyngeal Diseases

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224077
}}
{{medline-entry
|title=Age Influences Microglial Activation After Cuprizone-Induced Demyelination.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30297998
|abstract=Multiple sclerosis (MS) is a chronic inflammatory CNS disease, which causes demyelinated lesions and damages white and gray matter regions. Aging is a significant factor in the progression of MS, and microglia, the immune cells of the CNS tissue, play an important role in all disease stages. During aging, microglia are functionally altered. These age-related changes probably already begin early and might influence the progression of CNS pathologies. The aim of the present study was to investigate whether microglia in the middle-aged CNS already react differently to demyelination. For this purpose, several microglia markers (ionized calcium binding adaptor molecule 1 (Iba-1), [[P2RY12]], F4/80, [[CD68]], major histocompatibility complex II (MHCII), macrophage receptor with collagenous structure (Marco), Translocator protein 18 kD ([[[[TSPO]]]]), CD206, and [[CD163]]) were analyzed in the acute cuprizone demyelination model in young (2-month-old) and middle-aged (10-month-old) mice. In addition, microglial proliferation was quantified using double-labeling with proliferating cell nuclear antigen ([[PCNA]]) and bromodeoxyuridine (BrdU), which was injected with the onset of remyelination. To compare age-related microglial changes during de- and remyelination in both gray and white matter, the hilus of the dorsal hippocampal dentate gyrus (DG) and the splenium of the corpus callosum (CC) were analyzed in parallel. Age-related changes in microglia of healthy controls were more pronounced in the analyzed gray matter region (higher levels of F4/80 and Marco as well as lower expression of [[CD68]] in middle-aged mice). During de- and remyelination, a stronger increase of the microglial markers Iba-1, [[CD68]] and [[[[TSPO]]]] was observed in the splenium of the younger groups. There was a significant reduction of [[P2RY12]] during demyelination, however, this was age- and region-dependent. The induction of the anti-inflammatory markers CD206 and [[CD163]] was stronger in the middle-aged group, but also differed between the two analyzed regions. De- and remyelination led to a significant increase in [[PCNA]]  microglia only in young groups within the white matter region. The number of BrdU  microglia was not changed during de- or remyelination. These results clearly show that microglia are already altered during middle-age and also react differently to CNS demyelination, however, this is highly region-dependent.

|keywords=* P2RY12
* TSPO
* aging
* corpus callosum
* cuprizone
* demyelination
* hippocampus
* microglia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160739
}}
{{medline-entry
|title=Pathology and Distribution of Trombiculosis in Northern Chamois ( Rupicapra rupicapra rupicapra) in the Italian Alps.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30161018
|abstract=Trombiculosis has been reported in some wild ruminant species. We investigated the occurrence of trombiculosis in the northern chamois ( Rupicapra rupicapra rupicapra) in the Western Italian Alps, and we describe the related histopathologic changes. Superficial scrapes and skin samples were taken from 191 chamois from the Lombardy and Piedmont regions during the hunting season in September-December 2015. Numbers of eosinophils, mast cells, cluster of differentiation (CD)3-, CD79α-, [[CD68]]-positive cells were determined on immunohistochemically stained skin sections using a semiautomatic analysis system. Forty (20.9, 40/191) chamois were positive for trombiculid larvae on skin scrapings. Of the positive animals, 15 were from Lombardy and 25 from Piedmont, with similar prevalences. Macroscopic lesions were light with involvement of body regions that had contact with the ground, especially head (pinnae and areas around eyes and mouth) and limbs, where stylostome was easily formed due to thin skin. Histologically, trombiculosis caused a focal moderate dermatitis with epidermal necrosis, thin crusts, and hyperkeratosis. Inflammatory infiltrates were suggestive of a granulomatous reaction centered on a stylostome, formed by mite saliva and necrotic host tissue debris. However, we detected some difference in cutaneous immune response with some chamois showing a prevalent T-cell response and others having an increased B-cell count associated with a higher number of eosinophils, mast cells and a lower number of T cells.
|mesh-terms=* Aging
* Animal Distribution
* Animals
* Female
* Italy
* Male
* Rupicapra
* Trombiculiasis
* Trombiculidae
|keywords=* Chiggers
* Trombiculidae
* dermatitis
* histopathology
* larval mites
* northern chamois
* trombiculosis
|full-text-url=https://sci-hub.do/10.7589/2018-01-020
}}
{{medline-entry
|title=Stem Cell-Induced Pulp Regeneration Can Be Enhanced by Administration of [[CCL11]]-Neutralizing Antibody in the Ectopic Tooth Transplantation Model in the Aged Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29962294
|abstract=Pulp regeneration by stem cell transplantation declines due to age-related reduction. We hypothesized that administration of a cytokine together with the cell transplantation may improve the stem cell niche microenvironment and promote regeneration. [[CCL11]] is implicated as a factor in aging. This investigation was performed to investigate the changes in the quality of the regenerated pulp by administration of [[CCL11]] antibody in the aged mice and elucidate the underlying mechanisms. Mobilized dental pulp stem cell (MDPSC) transplants were characterized in an ectopic tooth root transplantation model in both the aged and young mice. The amount of regenerated pulp tissue was analyzed in the transplants with continuous administration of [[CCL11]] antibody compared with those without the antibody administration. Blood [[CCL11]] levels were assessed at the onset of the experiment. Furthermore, immunostaining of [[CD68]] together with CD11c or CD206 for M1 and M2 macrophage, respectively, were performed. Each double-positive cell count of M1 and M2 macrophages and M1/M2 ratio in the transplants with administration were compared with those without administration both in the aged and young mice. The administration of [[CCL11]] antibody enhanced pulp regeneration and significantly reduced the blood [[CCL11]] level in the aged mice. As the number of M1 macrophages decreased, the M1/M2 ratio in the treated aged mouse was less than that in the untreated aged mouse. There was, however, significant difference between the treated aged mouse and the untreated young mouse. [[CCL11]] antibody has the potential to enhance and stimulate pulp regeneration in the aged mice.
|mesh-terms=* Aging
* Animals
* Antibodies, Neutralizing
* Cell Differentiation
* Chemokine CCL11
* Dental Pulp
* Mice
* Mice, SCID
* Regeneration
* Stem Cell Transplantation
* Stem Cells
* Swine
* Tooth Replantation
|keywords=* growth factor
* regeneration
* rejuvenation
* stem cells
|full-text-url=https://sci-hub.do/10.1089/rej.2018.2064
}}
{{medline-entry
|title=Pro- and Anti-inflammatory Effects of High Cholesterol Diet on Aged Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29896426
|abstract=Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer's disease. However, their interactive influence on the neurodegenerative progress remains unclear. To address this issue, 6-month-old and 16-month-old female mice were fed a 3% cholesterol diet for 8 weeks, followed by hippocampus-related functional, pathological, biochemical and molecular analyses. The high cholesterol diet did not exacerbate age-dependent cognitive decline and hippocampal neuronal death, and even greatly mitigated decreases of synaptophysin and growth associated protein 43 expression in the hippocampus of aged mice. Compared with young controls, aged mice fed normal diet showed mild activation of hippocampal microglia with increased expression of [[CD68]], a marker of the microglial M1 phenotype, and decreased expression of CD206, a marker of the microglial M2 phenotype. More interestingly, the high cholesterol diet not only improved [[NLRP3]] inflammasome activation and IL-1β expression, but also increased levels of anti-inflammatory cytokines IL-4 and IL-6 in the hippocampus of old mice, suggesting playing pro- and anti-neuroinflammatory effects. In addition, the cholesterol rich diet resulted in a defect of the blood-brain barrier of aged hippocampus, as revealed by increased brain albumin content. These results have revealed both harmful and protective effects of high cholesterol diet on aged brain, which helps us to understand that hypercholesterolemia in the aged population is not associated with dementia and cognitive impairment.

|keywords=* aging
* brain
* high cholesterol diet
* neuroinflammation
* synaptic proteins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988593
}}
{{medline-entry
|title=Chia Seed Supplementation Reduces Senescence Markers in Epididymal Adipose Tissue of High-Fat Diet-Fed SAMP8 Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29652550
|abstract=Adipose tissue is a key organ with substantial senescent cell accumulation under both obesity and aging conditions. Chia seed is an ancient seed and is the richest plant source of α-linolenic acid. We aimed to determine how cellular senescence markers will be altered in adipose tissue of senescence-accelerated mouse-prone 8 (SAMP8) mice fed with high-fat diets (HFDs); and how chia seed can affect the above markers. SAMP8 mice and their control senescence-accelerated mouse-resistant 1 (SAMR1) were divided into four groups, that is, SAMR1 low-fat diet group (R1LF), SAMP8LF group (P8LF), SAMP8 high-fat group (P8HF), and SAMP8HF group supplemented with 10% chia seed (P8HC). At the end of the intervention, body composition was measured through T -weighted magnetic resonance imaging, and epididymal (EPI) and subcutaneous (SC) adipose tissues were dissected for further analysis. Compared with the R1LF group, the P8HF and P8HC groups had significantly increased body fat mass. In EPI fat, p16, [[CD68]] and PAI-1 mRNA expression from P8HF group were significantly increased; chia seed partially reduced p16 and [[CD68]] mRNA expression. The P8LF group has increased p16 and [[CD68]], and the P8HF group has increased p16, p21, and [[CD68]]; and P8HC group has increased p16 mRNA expression. The protein expression of p-AMPK in EPI and SC fat from the P8HF group was reduced. In conclusion, reductions in AMPK activity might be partially responsible for elevation in HFD-induced senescence markers in both EPI and SC fat, and chia seed supplementation is able to reduce senescence-associated markers at least in EPI adipose tissue.
|mesh-terms=* Adipose Tissue
* Aging
* Animals
* Body Composition
* Diet, High-Fat
* Dietary Supplements
* Disease Models, Animal
* Epididymis
* Male
* Mice
* Mice, Obese
* Obesity
* Phytotherapy
* Salvia
* Seeds
|keywords=* adipose tissue
* chia seed
* high-fat diet
* senescence
|full-text-url=https://sci-hub.do/10.1089/jmf.2017.4129
}}
{{medline-entry
|title=Lifelong environmental enrichment in the absence of exercise protects the brain from age-related cognitive decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29630903
|abstract=Environmental manipulations enhance neuroplasticity, with enrichment-induced cognitive improvements linked to increased expression of growth factors and enhanced hippocampal neurogenesis. Environmental enrichment (EE) is defined as the addition of social, physical and somatosensory stimulation into an animal's environment via larger group housing, extra objects and, often, running wheels. Previous studies from our laboratory report that physical activity is a potent memory enhancer but that long-term environmental stimulation can be as effective as exercise at ameliorating age-related memory decline. To assess the effects of EE, in the absence of exercise, rats were housed in continuous enriched conditions for 20 months and memory assessed at young, middle aged and aged timepoints. MRI scans were also performed at these timepoints to assess regional changes in grey matter and blood flow with age, and effects of EE upon these measures. Results show an age-related decline in recognition, spatial and working memory that was prevented by EE. A parallel reduction in βNGF in hippocampus, and cell proliferation in the dentate gyrus, was prevented by EE. Furthermore, EE attenuated an age-related increase in apoptosis and expression of pro-inflammatory markers IL-1β and [[CD68]]. Long-term EE induced region-specific changes in grey matter intensity and partially rescued age-related reductions in cerebral blood flow. This study demonstrates that sensory enrichment alone can ameliorate many features typical of the ageing brain, such as increases in apoptosis and pro-inflammatory markers. Furthermore, we provide novel data on enrichment-induced regional grey matter alterations and age-related changes in blood flow in the rat. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".
|mesh-terms=* Animals
* Anxiety
* Apoptosis
* Brain
* Cognition
* Cognitive Aging
* Cognitive Dysfunction
* Disease Resistance
* Environment
* Exploratory Behavior
* Housing, Animal
* Inflammation
* Male
* Neurogenesis
* Random Allocation
* Rats, Wistar
* Recognition, Psychology
* Spatial Memory
|keywords=* Ageing
* Environmental enrichment
* Learning and memory
* Nerve growth factor
* Neurogenesis
|full-text-url=https://sci-hub.do/10.1016/j.neuropharm.2018.03.042
}}
{{medline-entry
|title=Age Dependent Hypothalamic and Pituitary Responses to Novel Environment Stress or Lipopolysaccharide in Rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29615881
|abstract=Previously, we have shown that the transcription factor nuclear factor interleukin (NF-IL)6 can be used as an activation marker for inflammatory lipopolysaccharide (LPS)-induced and psychological novel environment stress ([[NES]]) in the rat brain. Here, we aimed to investigate age dependent changes of hypothalamic and pituitary responses to [[NES]] (cage switch) or LPS (100 μg/kg) in 2 and 24 months old rats. Animals were sacrificed at specific time points, blood and brains withdrawn and analyzed using immunohistochemistry, RT-PCR and bioassays. In the old rats, telemetric recording revealed that [[NES]]-induced hyperthermia was enhanced and prolonged compared to the young group. Plasma IL-6 levels remained unchanged and hypothalamic IL-6 mRNA expression was increased in the old rats. Interestingly, this response was accompanied by a significant upregulation of corticotropin-releasing hormone mRNA expression only in young rats after [[NES]] and overall higher plasma corticosterone levels in all aged animals. Immunohistochemical analysis revealed a significant upregulation of NF-[[IL6]]-positive cells in the pituitary after [[NES]] or LPS-injection. In another important brain structure implicated in immune-to-brain communication, namely, in the median eminence (ME), NF-[[IL6]]-immunoreactivity was increased in aged animals, while the young group showed just minor activation after LPS-stimulation. Interestingly, we found a higher amount of NF-[[IL6]]-[[CD68]]-positive cells in the posterior pituitary of old rats compared to the young counterparts. Moreover, aging affected the regulation of cytokine interaction in the anterior pituitary lobe. LPS-treatment significantly enhanced the secretion of the cytokines IL-6 and TNFα into supernatants of primary cell cultures of the anterior pituitary. Furthermore, in the young rats, incubation with IL-6 and IL-10 antibodies before LPS-stimulation led to a robust decrease of IL-6 production and an increase of TNFα production by the pituitary cells. In the old rats, this specific cytokine interaction could not be detected. Overall, the present results revealed strong differences in the activation patterns and pathways between old and young rats after both stressors. The prolonged hyperthermic and inflammatory response seen in aged animals seems to be linked to dysregulated pituitary cytokine interactions and brain cell activation (NF-[[IL6]]) in the hypothalamus-pituitary-adrenal axis.

|keywords=* NF-IL6
* aging
* cage switch
* fever
* hyperthermia
* immune-to-brain communication
* lipopolysaccharide
* novel environment stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868128
}}
{{medline-entry
|title=Secreted Klotho Attenuates Inflammation-Associated Aortic Valve Fibrosis in Senescence-Accelerated Mice P1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29581213
|abstract=Senescence-accelerated mice P1 (SAMP1) is an aging model characterized by shortened lifespan and early signs of senescence. Klotho is an aging-suppressor gene. The purpose of this study is to investigate whether in vivo expression of secreted klotho ([i]Skl[/i]) gene attenuates aortic valve fibrosis in SAMP1 mice. SAMP1 mice and age-matched (AKR/J) control mice were used. SAMP1 mice developed obvious fibrosis in aortic valves, namely fibrotic aortic valve disease. Serum level of Skl was decreased drastically in SAMP1 mice. Expression of MCP-1 (monocyte chemoattractant protein 1), ICAM-1 (intercellular adhesion molecule 1), F4/80, and [[CD68]] was increased in aortic valves of SAMP1 mice, indicating inflammation. An increase in expression of α-smooth muscle actin (myofibroblast marker), transforming growth factorβ-1, and scleraxis (a transcription factor of collagen synthesis) was also found in aortic valves of SAMP1 mice, suggesting that accelerated aging is associated with myofibroblast transition and collagen gene activation. We constructed adeno-associated virus 2 carrying mouse Skl cDNA for in vivo expression of Skl. [i]Skl[/i] gene delivery effectively increased serum Skl of SAMP1 mice to the control level. [i]Skl[/i] gene delivery inhibited inflammation and myofibroblastic transition in aortic valves and attenuated fibrotic aortic valve disease in SAMP1 mice. It is concluded that senescence-related fibrotic aortic valve disease in SAMP1 mice is associated with a decrease in serum klotho leading to inflammation, including macrophage infiltration and transforming growth factorβ-1/scleraxis-driven myofibroblast differentiation in aortic valves. Restoration of serum Skl levels by adeno-associated virus 2 carrying mouse Skl cDNA effectively suppresses inflammation and myofibroblastic transition and attenuates aortic valve fibrosis. Skl may be a potential therapeutic target for fibrotic aortic valve disease.
|mesh-terms=* Aging
* Analysis of Variance
* Animals
* Aortic Valve
* Aortic Valve Stenosis
* Bicuspid Aortic Valve Disease
* Biopsy, Needle
* Disease Models, Animal
* Down-Regulation
* Fibrosis
* Gene Expression Regulation
* Heart Defects, Congenital
* Heart Valve Diseases
* Immunohistochemistry
* Intercellular Adhesion Molecule-1
* Longevity
* Membrane Proteins
* Mice
* Mice, Inbred Strains
* Random Allocation
* Sensitivity and Specificity
* Vascular Stiffness
|keywords=* actins
* aortic valve
* collagen
* immunity
* inflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897144
}}
{{medline-entry
|title=Salidroside attenuates endothelial cellular senescence via decreasing the expression of inflammatory cytokines and increasing the expression of [[SIRT3]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29289557
|abstract=Endothelial cellular senescence is an important contributor to the endothelial dysfunction and atherosclerosis. Our previous studies suggested that salidroside (SAL) can alleviate atherosclerosis and protect endothelial cells against oxidative stress induced damage. However, the effect and mechanism of SAL on endothelial cellular senescence is still unclear. Here, we investigated the underlying mechanisms of SAL on preventing endothelial cellular premature senescence. We established a hyperhomocysteinemia (HHcy)mouse model via high methionine diet (HMD) to explore the protective effect of SAL. According to our results, the HMD elevated the concentration of serum homocysteine. HHcy induced the collagen deposition and the up-regulation of senescence markers, i.e. p16  and p21 , in intima-medial of aorta. In addition, SAL also inhibited the expression of [[CD68]] and intercellular adhesion molecule 1 (ICAM1) in aorta. In senescent human umbilical vein endothelial cells (HUVECs) induced by H O , SAL treatment alleviated the expression of p16  and p21  and reduced the activity of senescence-associated (SA)-β-gal. our data suggested that SAL decreased the expression of inflammatory cytokines and up-regulated the expression of [[SIRT3]], which might be the underlying mechanism of SAL on preventing endothelial cells from premature senescence.
|mesh-terms=* Animals
* Anti-Inflammatory Agents
* Aorta
* Cells, Cultured
* Cellular Senescence
* Collagen
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Cytokines
* Disease Models, Animal
* Glucosides
* Human Umbilical Vein Endothelial Cells
* Humans
* Hyperhomocysteinemia
* Inflammation Mediators
* Male
* Mice, Inbred BALB C
* Phenols
* Sirtuin 3
* Up-Regulation
* Vascular Remodeling
* beta-Galactosidase
|keywords=* Endothelial cellular senescence
* Inflammatory cytokines
* SIRT3
* Salidroside
|full-text-url=https://sci-hub.do/10.1016/j.mad.2017.12.005
}}
{{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=Morphological alterations in the jejunal mucosa of aged rats and the possible protective role of green tea.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28813122
|abstract=Gastrointestinal disorders become more prevalent with ageing. This study is aimed to describe morphological changes that occur in the jejunal mucosa of male albino rats as a result of ageing and the protec-tive effect of green tea (GT) extract. The experiment was performed on sixty rats: thirty young-adult (6-month old, body mass 200-220 g) and thirty old (24-month-old, body mass 220-260 g) animals. Each group was further divided into two subgroups (n = 15 each): control rats and GT-treated rats that received 1.5 mL (300 mg/kg/day) of GT extract for 14 weeks by oral gavage. Sections of the jejunum were stained with hematoxylin and eosin, periodic acid Schiff, toluidine blue and Mallory trichrome methods. The presence of proliferating cell nuclear antigen ([[PCNA]])- and [[CD68]]-positive cells was evaluated by immunohistochemical staining. Ultrathin sections were prepared and examined by a transmission electron microscope (TEM). Jejunal sections of the old control rats showed distortion of submucosa and attenuated muscularis externa with decreased height of intestinal villi. The villi also showed partial loss of acidophilic brush border with wide spaces between enterocytes. Swollen, short, blunt or broad villi with abundant mononuclear cell infiltration of lamina propria and congested blood vessels were evident both by light and electron microscopy. The number of [[PCNA]]- and [[CD68]]-positive cells in jejunal mucosa of old rats was higher than in young rats. The activity of glutathione peroxidase (GPX) and total antioxidant capacity (TAC) in the mucosa of old control rats were lower, whereas malondialdehyde (MDA) levels were higher in the jejunal homogenates of old rats as compared to young control rats. Administration of GT extract protected the jejunal mucosa from age-related changes by restoring its histological structure. The treatment of old rats with GT extract significantly decreased MDA levels in the jejunum and increased TAC and GPX activity. The age-related changes of the morphology of rat jejunum could be ameliorated by prolonged supplementation of the green tea extract.
|mesh-terms=* Age Factors
* Animals
* Antioxidants
* Immunohistochemistry
* Intestinal Mucosa
* Jejunum
* Male
* Rats
* Tea
|keywords=* CD68
* IHC
* PCNA
* TEM
* aging
* green tea
* jejunal mucosa
* morphology
* rat
|full-text-url=https://sci-hub.do/10.5603/FHC.a2017.0012
}}
{{medline-entry
|title=Increased White Matter Inflammation in Aging- and Alzheimer's Disease Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28713239
|abstract=Chronic neuroinflammation, which is primarily mediated by microglia, plays an essential role in aging and neurodegeneration. It is still unclear whether this microglia-induced neuroinflammation occurs globally or is confined to distinct brain regions. In this study, we investigated microglia activity in various brain regions upon healthy aging and Alzheimer's disease (AD)-related pathology in both human and mouse samples. In purified microglia isolated from aging mouse brains, we found a profound gene expression pattern related to pro-inflammatory processes, phagocytosis, and lipid homeostasis. Particularly in white matter microglia of 24-month-old mice, abundant expression of phagocytic markers including Mac-2, Axl, CD16/32, Dectin1, CD11c, and [[CD36]] was detected. Interestingly, in white matter of human brain tissue the first signs of inflammatory activity were already detected during middle age. Thus quantification of microglial proteins, such as [[CD68]] (commonly associated with phagocytosis) and HLA-DR (associated with antigen presentation), in postmortem human white matter brain tissue showed an age-dependent increase in immunoreactivity already in middle-aged people (53.2 ± 2.0 years). This early inflammation was also detectable by non-invasive positron emission tomography imaging using [ C]-(R)-PK11195, a ligand that binds to activated microglia. Increased microglia activity was also prominently present in the white matter of human postmortem early-onset AD (EOAD) brain tissue. Interestingly, microglia activity in the white matter of late-onset AD (LOAD) CNS was similar to that of the aged clinically silent AD cases. These data indicate that microglia-induced neuroinflammation is predominant in the white matter of aging mice and humans as well as in EOAD brains. This white matter inflammation may contribute to the progression of neurodegeneration, and have prognostic value for detecting the onset and progression of aging and neurodegeneration.

|keywords=* Alzheimer’s disease
* aging
* microglia
* neuroinflammation
* white matter
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492660
}}
{{medline-entry
|title=Aging-related effects of bed rest followed by eccentric exercise rehabilitation on skeletal muscle macrophages and insulin sensitivity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28705613
|abstract=The pro- and anti-inflammatory macrophages are associated with insulin sensitivity and skeletal muscle regeneration. Infiltrating macrophages in skeletal muscle during a period of physical inactivity and subsequent reloading/rehabilitation in older adults is unknown, but may provide insight into mechanisms related to the development of metabolic disease and changes in muscle cell size. The purpose of this study was to determine if skeletal muscle macrophage infiltration is modulated differently between young and older adults after bed rest and exercise rehabilitation and if these responses are related to muscle and insulin sensitivity changes. 14 young and 9 older adults underwent 5-days of bed rest followed by 8-weeks of lower limb eccentric exercise rehabilitation (REHAB). Dual-energy X-ray absorptiometry, magnetic resonance imaging and myofiber analysis were used to identify muscle morphology and CLIX-IR and CLIX-β were used to assess insulin sensitivity. Skeletal muscle macrophages, [[CD68]] (pan), CD11b (M1), [[CD163]] (M2), CD206 (M2), were characterized using immunohistochemistry and gene expression. Insulin sensitivity, independent of age, decreased ~38% following bed rest and was restored following REHAB. We found robust age-related differences in muscle atrophy during bed rest, yet older and younger adults equally hypertrophied during REHAB. Interestingly, there were age-related differences in macrophage content ([[CD68]] CD11b  and [[CD68]] CD11b  cells) but both young and old similarly increased macrophages with REHAB. Satellite cell changes during rehab corresponded to macrophage content changes. Muscle tissue resident macrophages and gene expression, were not associated with changes in insulin sensitivity following bed rest and REHAB. These data suggest that muscle macrophages are modulated as a result of exercise rehabilitation following bed rest and may more associated with muscle regrowth/hypertrophy rather than insulin sensitivity in young or older adults. This trial was registered at clinicaltrials.gov as NCT01669590.
|mesh-terms=* Absorptiometry, Photon
* Adolescent
* Adult
* Age Factors
* Aged
* Antigens, CD
* Bed Rest
* Case-Control Studies
* Exercise
* Exercise Therapy
* Female
* Gene Expression
* Humans
* Insulin Resistance
* Macrophages
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Muscle, Skeletal
* Muscular Atrophy
* Prospective Studies
* Young Adult
|keywords=* Aging
* Atrophy
* Eccentric exercise
* Immune cells
* M1
* M2
* Muscle-resident
* Recovery
* Regrowth
* Rehabilitation
* Training
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762440
}}
{{medline-entry
|title=Involvement of progranulin in modulating neuroinflammatory responses but not neurogenesis in the hippocampus of aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28479389
|abstract=It is well established that adult neurogenesis in the hippocampus declines with age. Our previous studies have suggested that progranulin (PGRN) has a facilitative effect on hippocampal neurogenesis. We have also shown that PGRN plays a role in suppressing excessive neuroinflammatory responses in the cortex and thalamus after brain injury and aging, respectively. However, the roles of PGRN in modulating neurogenesis and neuroinflammatory responses in the hippocampus of aged animals are not yet understood. In the present study, we investigated neurogenesis and neuroinflammation-related responses in the hippocampus of young (15-week-old) and old (135-week-old) wild-type and PGRN-deficient male mice. Neurogenesis in the dentate gyrus of the hippocampus markedly declined with age, and there was no significant difference between the genotype. The number of [[CD68]]-positive activated microglia and the expression of lysosomal genes in the hippocampus were significantly increased with age, and PGRN deficiency further increased them. The expression of pro-inflammatory genes was also increased with age, and PGRN deficiency significantly enhanced some of them. These results suggest that PGRN deficiency exacerbates neuroinflammatory responses related to activated microglia in aged animals, while PGRN may not counteract the decline of hippocampal neurogenesis with age.
|mesh-terms=* Age Factors
* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Dentate Gyrus
* Encephalitis
* Granulins
* Hippocampus
* Inflammation Mediators
* Intercellular Signaling Peptides and Proteins
* Lysosomes
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Microglia
* Neurogenesis
* Progranulins
|keywords=* Aging
* Hippocampus
* Neurogenesis
* Neuroinflammation
* Progranulin
|full-text-url=https://sci-hub.do/10.1016/j.exger.2017.05.003
}}
{{medline-entry
|title=Microglia density decreases in the rat rostral nucleus of the solitary tract across development and increases in an age-dependent manner following denervation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28478126
|abstract=Microglia are critical for developmental pruning and immune response to injury, and are implicated in facilitating neural plasticity. The rodent gustatory system is highly plastic, particularly during development, and outcomes following nerve injury are more severe in developing animals. The mechanisms underlying developmental plasticity in the taste system are largely unknown, making microglia an attractive candidate. To better elucidate microglia's role in the taste system, we examined these cells in the rostral nucleus of the solitary tract (rNTS) during normal development and following transection of the chorda tympani taste nerve (CTX). Rats aged 5, 10, 25, or 50days received unilateral CTX or no surgery and were sacrificed four days later. Brain tissue was stained for Iba1 or [[CD68]], and both the density and morphology of microglia were assessed on the intact and transected sides of the rNTS. We found that the intact rNTS of neonatal rats (9-14days) shows a high density of microglia, most of which appear reactive. By 29days of age, microglia density significantly decreased to levels not significantly different from adults and microglia morphology had matured, with most cells appearing ramified. [[CD68]]-negative microglia density increased following CTX and was most pronounced for juvenile and adult rats. Our results show that microglia density is highest during times of normal gustatory afferent pruning. Furthermore, the quantity of the microglia response is higher in the mature system than in neonates. These findings link increased microglia presence with instances of normal developmental and injury induced alterations in the rNTS.
|mesh-terms=* Age Factors
* Aging
* Analysis of Variance
* Animals
* Animals, Newborn
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Autonomic Denervation
* Calcium-Binding Proteins
* Cell Count
* Chorda Tympani Nerve
* Female
* Male
* Microfilament Proteins
* Microglia
* Rats
* Rats, Sprague-Dawley
* Solitary Nucleus
* Time Factors
|keywords=* CD68
* chorda tympani transection
* gustatory development
* immune response to injury
* microglia
* nucleus of the solitary tract
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502742
}}
{{medline-entry
|title=Inhomogeneous distribution of Iba-1 characterizes microglial pathology in Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27404378
|abstract=Microglial dystrophy has recently been described as a morphological phenotype of microglia that differs from resting and activated states by spheroid formation and cytorrhexis. In thick sections immunolabeled for HLA-DR or Iba-1 dystrophic microglial processes lose their typical, homogeneous staining pattern and appear to be fragmented or clustered. In this study, we performed double immunofluorescence and electron microscopy to determine if this labeling pattern indeed reflects complete separation of microglial processes from the soma. Using Iba-1/[[CD68]] and Iba-1/MHC class II, as microglial markers, we observed that isolated Iba-1 fragments were still connected to each other by segments of the microglial process immune positive for [[CD68]] or MHC class II. Ultrathin serial sections of two Iba-1 fragments which appeared to be disconnected from each other at the light microscopical level revealed a still existing "bridge" with a diameter of around 0.182 µm. Therefore, microglial dystrophy may reflect alterations of the cytoskeleton ultimately leading to slow cytorrhexis. GLIA 2016;64:1562-1572.
|mesh-terms=* Aged
* Aged, 80 and over
* Alzheimer Disease
* Biomarkers
* Brain
* Calcium-Binding Proteins
* DNA-Binding Proteins
* Female
* Humans
* Immunohistochemistry
* Male
* Microfilament Proteins
* Microglia
* Middle Aged
* Neurons
|keywords=* Alzheimer's disease
* Iba-1
* cytorrhexis
* glial pathology
* microglia
* neurodegeneration
* senescence
|full-text-url=https://sci-hub.do/10.1002/glia.23024
}}
{{medline-entry
|title=Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in [[S100B]] knockout mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26907191
|abstract=[[S100B]] is a calcium-sensor protein that impacts multiple signal transduction pathways. It is widely considered to be an important biomarker for several neuronal diseases as well as blood-brain barrier (BBB) breakdown. In this report, we demonstrate a BBB deficiency in mice that lack [[S100B]] through detection of leaked Immunoglobulin G (IgG) in the brain parenchyma. IgG leaks and IgG-binding to selected neurons were observed in [[S100B]] knockout ([[S100B]]KO) mice at 6 months of age but not at 3 months. By 9 months, IgG leaks persisted and the density of IgG-bound neurons increased significantly. These results reveal a chronic increase in BBB permeability upon aging in [[S100B]]KO mice for the first time. Moreover, coincident with the increase in IgG-bound neurons, autoantibodies targeting brain proteins were detected in the serum via western blots. These events were concurrent with compromise of neurons, increase of activated microglia and lack of astrocytic activation as evidenced by decreased expression of microtubule-associated protein type 2 (MAP2), elevated number of [[CD68]] positive cells and unaltered expression of glial fibrillary acidic protein (GFAP) respectively. Results suggest a key role for [[S100B]] in maintaining BBB functional integrity and, further, propose the [[S100B]]KO mouse as a valuable model system to explore the link between chronic functional compromise of the BBB, generation of brain-reactive autoantibodies and neuronal dysfunctions. 
|mesh-terms=* Age Factors
* Animals
* Autoantibodies
* Blood-Brain Barrier
* Brain
* Immunoglobulin G
* Mice
* Mice, Knockout
* Microtubule-Associated Proteins
* Neurons
* Permeability
* S100 Calcium Binding Protein beta Subunit
|keywords=* Aging
* Autoantibodies
* Blood–brain barrier
* Neurodegenerative disease
* S100B
|full-text-url=https://sci-hub.do/10.1016/j.brainres.2016.02.026
}}
{{medline-entry
|title=Microglia in dementia with Lewy bodies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26518296
|abstract=Microglial activation (neuroinflammation) is often cited as a pathogenic factor in the development of neurodegenerative diseases. However, there are significant caveats associated with the idea that inflammation directly causes either α-synuclein pathology or neurofibrillary degeneration (NFD). We have performed immunohistochemical studies on microglial cells in five cases of dementia with Lewy bodies (DLB), median age 87, and nine cases of non-demented (ND) controls, median age 74, using tissue samples from the temporal lobe and the superior frontal gyrus. Three different antibodies known to label microglia and macrophages were employed: iba1, anti-[[CD68]], and anti-ferritin. All DLB cases showed both α-synuclein pathology (Lewy bodies and neurites) and NFD ranging from Braak stage II to IV. In contrast, all controls were devoid of α-synuclein pathology but did show NFD ranging from Braak stage I to III. Using iba1 labeling, our current results show a notable absence of activated microglia in all cases with the exception of two controls that showed small focal areas of microglial activation and macrophage formation. Both iba1 and ferritin antibodies revealed a mixture of ramified and dystrophic microglial cells throughout the regions examined, and there were no measurable differences in the prevalence of dystrophic microglial cells between DLB and controls. Double-labeling for α-synuclein and iba1-positive microglia showed that cortical Lewy bodies were surrounded by both ramified and dystrophic microglial cells. We found an increase in [[CD68]] expression in DLB cases relative to controls. Since microglial dystrophy has been linked to NFD and since it did not appear to be worse in DLB cases over controls, our findings support the idea that the additional Lewy body pathology in DLB is not the result of intensified microglial dystrophy. [[CD68]] is likely associated with lipofuscin deposits in microglial cells which may be increased in DLB cases because of impaired proteostasis. Overall, we conclude that neurodegenerative changes in DLB are unlikely to result directly from activated microglia but rather from dysfunctional ones.
|mesh-terms=* Aged
* Aged, 80 and over
* Female
* Humans
* Inflammation
* Lewy Body Disease
* Lipofuscin
* Male
* Microglia
* alpha-Synuclein
|keywords=* Lipofuscin
* Microglial activation
* Microglial dystrophy
* Microglial senescence
* Neurodegenerative disease
* Neuroinflammation
* α-Synuclein pathology
|full-text-url=https://sci-hub.do/10.1016/j.bbi.2015.10.012
}}
{{medline-entry
|title=The cricothyroid joint in elderly Japanese individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26286109
|abstract=Using 15 cricothyroid joint (CT joint) specimens obtained from donated cadavers of elderly individuals, we examined the morphologies of the ceratocricoid ligaments as well as the synovial tissue. The ligaments consistently contained abundant elastic fibers: the fibers tended to be straight on the anterior side in contrast to a mesh-like arrangement on the posterior side. Thick and/or long synovial folds were often evident in the CT joint. The synovial tissue usually contained [[CD68]]-positive macrophages, but the positive cells were often restricted to certain parts of the tissue. Factor VIII-positive capillaries were present but few in number, and CD3- or IgM-positive lymphocytes were absent in the synovial tissue. Degenerative changes in the joint cartilage, such as roughness or thinning, were often present, but no cartilage defects were evident. Therefore, in contrast to the small, non-weight-bearing joints of the musculoskeletal system, we considered the degeneration of the CT joint to be a specific, silent form of osteoarthritis. For high-pitched phonation and ossification of the laryngeal cartilage, the CT joint in elderly individuals seemed to maintain its anterior gliding and rotation with the aid of elastic fiber-rich tissues compensating for the loss of congruity between the joint cartilage surfaces. 
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Asian Continental Ancestry Group
* Cadaver
* Cricoid Cartilage
* Female
* Humans
* Ligaments, Articular
* Male
* Osteoarthritis
* Synovial Membrane
* Thyroid Cartilage
|keywords=* Ceratocricoid ligaments
* Cricothyroid joint
* Elastic fibers
* Immunohistochemistry
* Synovial fold
|full-text-url=https://sci-hub.do/10.1007/s12565-015-0294-x
}}
{{medline-entry
|title=Neuroimmune and Neuropathic Responses of Spinal Cord and Dorsal Root Ganglia in Middle Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26241743
|abstract=Prior studies of aging and neuropathic injury have focused on senescent animals compared to young adults, while changes in middle age, particularly in the dorsal root ganglia (DRG), have remained largely unexplored. 14 neuroimmune mRNA markers, previously associated with peripheral nerve injury, were measured in multiplex assays of lumbar spinal cord (LSC), and DRG from young and middle-aged (3, 17 month) naïve rats, or from rats subjected to chronic constriction injury (CCI) of the sciatic nerve (after 7 days), or from aged-matched sham controls. Results showed that [[CD2]], CD3e, [[CD68]], CD45, [[TNF]]-α, [[IL6]], [[CCL2]], [[ATF3]] and TGFβ1 mRNA levels were substantially elevated in LSC from naïve middle-aged animals compared to young adults. Similarly, LSC samples from older sham animals showed increased levels of T-cell and microglial/macrophage markers. CCI induced further increases in [[CCL2]], and [[IL6]], and elevated [[ATF3]] mRNA levels in LSC of young and middle-aged adults. Immunofluorescence images of dorsal horn microglia from middle-aged naïve or sham rats were typically hypertrophic with mostly thickened, de-ramified processes, similar to microglia following CCI. Unlike the spinal cord, marker expression profiles in naïve DRG were unchanged across age (except increased [[ATF3]]); whereas, levels of [[GFAP]] protein, localized to satellite glia, were highly elevated in middle age, but independent of nerve injury. Most neuroimmune markers were elevated in DRG following CCI in young adults, yet middle-aged animals showed little response to injury. No age-related changes in nociception (heat, cold, mechanical) were observed in naïve adults, or at days 3 or 7 post-CCI. The patterns of marker expression and microglial morphologies in healthy middle age are consistent with development of a para-inflammatory state involving microglial activation and T-cell marker elevation in the dorsal horn, and neuronal stress and satellite cell activation in the DRG. These changes, however, did not affect the establishment of neuropathic pain. 
|mesh-terms=* Age Factors
* Aging
* Animals
* Antigens, CD
* Cytokines
* Ganglia, Spinal
* Male
* Microglia
* Neuralgia
* Nociception
* Rats
* Satellite Cells, Perineuronal
* Sciatic Neuropathy
* Spinal Cord

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4524632
}}
{{medline-entry
|title=A chimeric Cfh transgene leads to increased retinal oxidative stress, inflammation, and accumulation of activated subretinal microglia in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26030099
|abstract=Variants of complement factor H (Cfh) affecting short consensus repeats (SCRs) 6 to 8 increase the risk of age-related macular degeneration. Our aim was to explore the effect of expressing a Cfh variant on the in vivo susceptibility of the retina and [[RPE]] to oxidative stress and inflammation, using chimeric Cfh transgenic mice (chCfhTg). The chCfhTg and age-matched C57BL/6J (B6) mice were subjected to oxidative stress by either normal aging, or by exposure to a combination of oral hydroquinone (0.8% HQ) and increased light. Eyes were collected for immunohistochemistry of [[RPE]]-choroid flat mounts and of retinal sections, ELISA, electron microscopy, and [[RPE]]/microglia gene expression analysis. Aging mice to 2 years led to an increased accumulation of basal laminar deposits, subretinal microglia/macrophages (MG/MΦ) staining for CD16 and for malondialdehyde (MDA), and MDA-modified proteins in the retina in chCfhTg compared to B6 mice. The chCfhTg mice maintained on HQ diet and increased light showed greater deposition of basal laminar deposits, more accumulation of fundus spots suggestive of MG/MΦ, and increased deposition of C3d in the sub-[[RPE]] space, compared to controls. In addition, chCfhTg mice demonstrated upregulation of [[NLRP3]], IP-10, [[CD68]], and TREM-2 in the RNA isolates from [[RPE]]/MG/MΦ. Expression of a Cfh transgene introducing a variant in SCRs 6 to 8 was sufficient to lead to increased retinal/[[RPE]] susceptibility to oxidative stress, a proinflammatory MG/MΦ phenotype, and a proinflammatory [[RPE]]/MG/MΦ gene expression profile in a transgenic mouse model. Our data suggest that altered interactions of Cfh with MDA-modified proteins may be relevant in explaining the effects of the Cfh variant.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Carrier Proteins
* Chemokine CXCL10
* Complement Factor H
* Disease Models, Animal
* Inflammation
* Membrane Glycoproteins
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Microglia
* NLR Family, Pyrin Domain-Containing 3 Protein
* Oxidative Stress
* Receptors, Immunologic
* Retina
* Retinal Pigment Epithelium

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464010
}}
{{medline-entry
|title=Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26001591
|abstract=Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer's disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions. Here we studied cases with pathologically-confirmed AD (n = 7), HS-Aging (n = 7), AD   HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer's Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and [[CD68]] (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD   HS-aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB. We conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Autopsy
* Calcium-Binding Proteins
* DNA-Binding Proteins
* Dementia
* Female
* Hippocampus
* Humans
* Lewy Body Disease
* Male
* Microfilament Proteins
* Microglia
* Sclerosis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489160
}}
{{medline-entry
|title=Telomere dysfunction reduces microglial numbers without fully inducing an aging phenotype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25892207
|abstract=The susceptibility of the aging brain to neurodegenerative disease may in part be attributed to cellular aging of the microglial cells that survey it. We investigated the effect of cellular aging induced by telomere shortening on microglia by the use of mice lacking the telomerase RNA component (TERC) and design-based stereology. TERC knockout (KO) mice had a significantly reduced number of CD11b( ) microglia in the dentate gyrus. Because of an even greater reduction in dentate gyrus volume, microglial density was, however, increased. Microglia in TERC KO mice maintained a homogenous distribution and normal expression of CD45 and [[CD68]] and the aging marker, ferritin, but were morphologically distinct from microglia in both adult and old wild-type mice. TERC KO mice also showed increased cellular apoptosis and impaired spatial learning. Our results suggest that individual microglia are relatively resistant to telomerase deficiency during steady state conditions, despite an overall reduction in microglial numbers. Furthermore, telomerase deficiency and aging may provide disparate cues leading to distinct changes in microglial morphology and phenotype.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Apoptosis
* Cellular Senescence
* Dentate Gyrus
* Ferritins
* Leukocyte Common Antigens
* Mice, Inbred C57BL
* Mice, Knockout
* Microglia
* Neurodegenerative Diseases
* Phenotype
* RNA
* Spatial Learning
* Telomerase
* Telomere
|keywords=* Cellular apoptosis
* Dentate gyrus
* Global spatial sampling
* Optical fractionator
* Replicative senescence
* Spatial learning
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2015.03.008
}}
{{medline-entry
|title=Temporal changes of [[CD68]] and α7 nicotinic acetylcholine receptor expression in microglia in Alzheimer's disease-like mouse models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25352454
|abstract=We previously reported that activated microglia are involved in amyloid-β (Aβ) clearance and that stimulation of α7 nicotinic acetylcholine receptors (nAChR) in microglia enhances Aβ clearance. Nevertheless, how microglia and α7 nAChR in microglia are affected in Alzheimer's disease (AD) remains unknown. The present study aimed to collect fundamental data for considering whether microglia are potential targets for AD treatment and the appropriate timing of therapeutic intervention, by evaluating the temporal changes of Aβ, microglia, neurons, presynapses, and α7 nAChR by immunohistochemical studies in mouse models of AD. In an Aβ-injected AD mouse model, we observed early accumulation of [[CD68]]-positive microglia at Aβ deposition sites and gradual reduction of Aβ. Microglia were closely associated with Aβ deposits, and were confirmed to participate in clearing Aβ. In a transgenic mouse model of AD, we observed an increase in Aβ deposition from 6 months of age, followed by a gradual increase in microglial accumulation at Aβ deposit sites. Activated microglia in APdE9 mice showed two-step transition: a [[CD68]]-negative activated form at 6-9 months and a [[CD68]]-positive form from 12 months of age. In addition, α7 nAChR in microglia increased markedly at 6 months of age when activated microglia appeared for the first time, and decreased gradually coinciding with the increase of Aβ deposition. These findings suggest that early microglial activation is associated with α7 nAChR upregulation in microglia in APdE9 mice. These novel findings are important for the development of new therapeutic strategy for AD. 
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Calcium-Binding Proteins
* Disease Models, Animal
* Disease Progression
* Enzyme-Linked Immunosorbent Assay
* Female
* Immunohistochemistry
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Microfilament Proteins
* Microglia
* Peptide Fragments
* Photomicrography
* Plaque, Amyloid
* Presynaptic Terminals
* Synaptophysin
* Time Factors
* alpha7 Nicotinic Acetylcholine Receptor
|keywords=* Alzheimer's disease
* CD68
* amyloid-β
* hippocampus
* injections
* microglia
* phagocytosis
* temporal
* transgenic
* α7 nAChR
|full-text-url=https://sci-hub.do/10.3233/JAD-141572
}}
{{medline-entry
|title=Lipid-laden partially-activated plasmacytoid and CD4(-)CD8α( ) dendritic cells accumulate in tissues in elderly mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25089147
|abstract=Aging is associated with a decline in lymphocyte function however, little is known about dendritic cell (DC) subsets and aging. Aging is also associated with increasing circulating lipid levels and intracellular lipid accumulation modulates DC function. Whether age-associated increases in lipid levels influence DC biology is unknown. Thus, the effects of aging on DC subsets were assessed in vivo using young adult and elderly C57BL/6 J mice. Major age-related changes included increased CD11c( ) DC numbers in lymph nodes, spleens and livers, but not lungs, and significantly increased proportions of plasmacytoid (pDC) and CD4(-)CD8α( ) DCs in lymph nodes and livers. Other changes included altered pDC activation status (decreased CD40, increased MHC class-I and MHC class-II), increased lipid content in pDCs and CD4(-)CD8α( ) DCs, and increased expression of key mediators of lipid uptake including lipoprotein lipase, scavenger receptors (CD36, [[CD68]] and LRP-1) in most tissues. Aging is associated with organ-specific numerical changes in DC subsets, and DC activation status, and increased lipid content in pDCs and CD4(-)CD8α( ) DCs. Up-regulation of lipoprotein lipase and scavenger receptors by lipid-rich pDCs and CD4(-)CD8α( ) DCs suggests these molecules contribute to DC lipid accumulation in the elderly. Lipid accumulation and modulated activation in pDCs and CD4(-)CD8α( ) DCs may contribute to the declining responses to vaccination and infection with age.

|keywords=* Aged mice
* Dendritic cell
* Immunosenescence
* Lipid uptake
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118209
}}
{{medline-entry
|title=Combined treatment of amyloid-β₁₋₄₂-stimulated bone marrow-derived dendritic cells plus splenocytes from young mice prevents the development of Alzheimer's disease in APPswe/PSENldE9 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25085784
|abstract=Anti-amyloid-β (Aβ) immunotherapy is a potential therapeutic strategy to reduce amyloid plaques and amyloid-associated pathologies in Alzheimer's disease (AD). Immune senescence with aging has also played a crucial role in AD pathogenesis and influences the effect of anti-Aβ immunotherapy. In this study, a combined treatment of Aβ₁₋₄₂-bone marrow-derived dendritic cells (BMDCs) with intraperitoneal injection of splenocytes from young mice was designed as a novel immunotherapy for AD in APPswe/PSEN1de9 transgenic mice models. The results showed that the combined treatment not only elevated the level of anti-Aβ antibodies but also reduced amyloid plaques in brain and finally ameliorated deterioration of spatial learning and memory in AD mice. Additionally, the results revealed an increase of [[CD68]] positive microglial cells in the vicinity of amyloid plaques in the mouse brain, which was responsible for the enhanced phagocytosis of Aβ plaques. In conclusion, the Aβ₁₋₄₂-BMDCs plus splenocytes treatment improved the phagocytosis of microglia and prevented AD pathology more effectively. This combined immunotherapy provided a promising treatment in preventing the progression of AD in clinical studies in the near future.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Bone Marrow Cells
* Brain
* Dendritic Cells
* Immunotherapy
* Injections, Intraperitoneal
* Mice
* Mice, Transgenic
* Microglia
* Peptide Fragments
* Phagocytosis
* Plaque, Amyloid
* Spleen
|keywords=* Alzheimer's disease
* Bone marrow derived dendritic cell
* Immune senescence
* Immunotherapy
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2014.06.029
}}
{{medline-entry
|title=Age-related changes in the optic nerve of Sprague-Dawley rats: an ultrastructural and immunohistochemical study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24958340
|abstract=The optic nerve is a unique part of the central nervous system. It lacks neuronal cell bodies and consists of axons of the retinal ganglion cells together with the supporting neuroglial cells. In the present study, aging of the optic nerve was studied in female Sprague-Dawley rats aged 3, 12, 24 and 30 months old, ultrastructurally, immunohistochemically and morphometrically trying to answer the question why aging is a common risk factor for many ocular diseases especially glaucoma. Additionally, studying the optic nerve aging offered a good opportunity to gain further insight into the effects of aging on white matter. Both nerve fibers and neuroglial cells demonstrated several age related changes which were more profound in 30 months old rats. Optic nerve axons displayed watery degeneration and dark degeneration. Myelin disturbances including widening, whorls, splitting and vacuolations of the myelin lamellae were also observed. Neuroglial cells appeared to be more frequent than in younger rats especially microglia cells and developed dense cytoplasmic inclusions. [[GFAP]]-positive astrocytes delineated age-related progressive increase in number, size as well as length and thickness of their processes. [[CD68]] immunohistochemical staining revealed age-related changes in the morphology, location and number of [[CD68]] positive microglia cells. 
|mesh-terms=* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Axons
* Cell Size
* Female
* Glial Fibrillary Acidic Protein
* Immunohistochemistry
* Optic Nerve
* Rats, Sprague-Dawley
|keywords=* Aging
* CD68
* GFAP
* Neuroglial cells
* Optic nerve
* Sprague-Dawley rats
* Ultrastructure
|full-text-url=https://sci-hub.do/10.1016/j.acthis.2014.05.001
}}
{{medline-entry
|title=Microglial cells in organotypic cultures of developing and adult mouse retina and their relationship with cell death.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24582572
|abstract=Organotypic cultures of retinal explants allow the detailed analysis of microglial cells in a cellular microenvironment similar to that in the in situ retina, with the advantage of easy experimental manipulation. However, the in vitro culture causes changes in the retinal cytoarchitecture and induces a microglial response that may influence the results of these manipulations. The purpose of this study was to analyze the influence of the retinal age on changes in retinal cytoarchitecture, cell viability and death, and microglial phenotype and distribution throughout the in vitro culture of developing and adult retina explants. Explants from developing (3 and 10 postnatal days, P3 and P10) and adult (P60) mouse retinas were cultured for up to 10 days in vitro (div). Dead or dying cells were recognized by TUNEL staining, cell viability was determined by flow cytometry, and the numbers and distribution patterns of microglial cells were studied by flow cytometry and immunocytochemistry, respectively. The retinal cytoarchitecture was better preserved at prolonged culture times (10 div) in P10 retina explants than in P3 or adult explants. Particular patterns of cell viability and death were observed at each age: in general, explants from developing retinas showed higher cell viability and lower density of TUNEL-positive profiles versus adult retinas. The proportion of microglial cells relative to the whole population of retinal cells was higher in explants fixed immediately after their dissection (i.e., non-cultured) from adult retinas than in those from developing retinas. This proportion was always higher in non-cultured explants than in explants at 10 div, suggesting the death of some microglial cells during the culture. Activation of microglial cells, as revealed by their phenotypical appearance, was observed in both developing and adult retina explants from the beginning of the culture. Immunofluorescence with the anti-[[CD68]] antibody showed that some activated microglial cells were [[CD68]]-positive but others were [[CD68]]-negative. Flow cytometry using [[CD68]]-labeling revealed that the percentage of [[CD68]]-positive microglial cells was much higher in developing than in adult retina explants, despite the activation of microglia in both types of explants, indicating that [[CD68]]-labeling was more closely related to the maturity degree of microglia than to their activation. Some swollen activated microglial cells entered the outer nuclear layer in developing and adult cultured retinal explants, whereas this layer was devoid of microglia in non-cultured explants. There was no apparent correlation between the distribution of microglia and that of TUNEL-labeled profiles. However, some swollen activated microglial cells in the outer and inner nuclear layers engulfed clusters of cell nuclei that were negative or weakly positive for TUNEL. This engulfment activity of microglia mimicked that observed in degenerative pathologies of the retina. We conclude that organotypic cultures from developing retinas show a higher rate of cell viability and better preservation of the normal cytoarchitecture in comparison to those obtained from adult retinas. In addition, the features of microglial response in cultured retinal explants show them to be a useful model for studying interactions between microglial cells and degenerating neurons in retinal diseases. 
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* CD11b Antigen
* Cell Death
* Cell Survival
* Flow Cytometry
* In Situ Nick-End Labeling
* Leukocyte Common Antigens
* Mice
* Mice, Inbred C57BL
* Microglia
* Organ Culture Techniques
* Retina
|keywords=* cell death
* cell viability
* microglia
* organotypic culture
* retina
|full-text-url=https://sci-hub.do/10.1016/j.exer.2014.02.015
}}
{{medline-entry
|title=Glutathione peroxidase-1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24296279
|abstract=Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1-deficient (GPx-1(-/-)) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1(-/-) mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1(-/-) -mice as compared with age-matched controls. Oxidant formation, detected by 3-nitrotyrosine staining and dihydroethidine-based fluorescence microtopography, was increased in the aged GPx-1(-/-) mice. Aging per se caused a substantial protein kinase C- and protein tyrosine kinase-dependent phosphorylation as well as S-glutathionylation of endothelial NO synthase associated with uncoupling, a phenomenon that was more pronounced in aged GPx-1(-/-) mice. GPx-1 ablation increased adhesion of leukocytes to cultured endothelial cells and [[CD68]] and F4/80 staining in cardiac tissue. Aged GPx-1(-/-) mice displayed increased oxidant formation as compared with their wild-type littermates, triggering redox-signaling pathways associated with endothelial NO synthase dysfunction and uncoupling. Thus, our data demonstrate that aging leads to decreased NO bioavailability because of endothelial NO synthase dysfunction and uncoupling of the enzyme leading to endothelial dysfunction, vascular remodeling, and promotion of adhesion and infiltration of leukocytes into cardiovascular tissue, all of which was more prominent in aged GPx-1(-/-) mice. 
|mesh-terms=* Aged
* Aging
* Animals
* Cells, Cultured
* Endothelial Cells
* Endothelium, Vascular
* Glutathione Peroxidase
* Humans
* Leukocytes
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Nitric Oxide Synthase Type III
* Oxidants
* Oxidative Stress
* Phosphorylation
|keywords=* aging
* oxidative stress
* vascular function
|full-text-url=https://sci-hub.do/10.1161/HYPERTENSIONAHA.113.01602
}}
{{medline-entry
|title=Postnatal early overnutrition causes long-term renal decline in aging male rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24232634
|abstract=We evaluated the influence of postnatal early overnutrition on renal pathophysiological changes in aging rats. Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (control) groups, respectively, during the first 21 d of life. The effects of early postnatal overnutrition were determined at 12 mo. SL rats weighed more than controls between 4 d and 6 mo of age (P < 0.05). However, between 6 and 12 mo, body weights in both groups were not different. In the SL group, at 12 mo, systolic blood pressure was higher and creatinine clearance was lower than the same in controls (P < 0.05). Numbers of [[CD68]] (ED1)-positive macrophages and apoptotic cells in renal cortex were higher in SL rats (P < 0.05). Furthermore, index scores for glomerulosclerosis and tubulointerstitial fibrosis were higher in the SL group (P < 0.05). Significantly less glomeruli per section area were found in aging SL rats (P < 0.05). Immunoblotting and immunohistochemistry showed decreased intrarenal renin expression in SL rats (P < 0.05). Early postnatal overnutrition can potentiate structural and functional abnormalities in the aging kidney and can lead to systolic hypertension with reduced intrarenal renin activity.
|mesh-terms=* Aging
* Animal Nutrition Sciences
* Animals
* Animals, Newborn
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Apoptosis
* Body Weight
* Creatinine
* Gene Expression Regulation
* Kidney
* Kidney Diseases
* Kidney Glomerulus
* Macrophages
* Male
* Overnutrition
* Rats
* Renin
* Systole
* Time Factors

|full-text-url=https://sci-hub.do/10.1038/pr.2013.223
}}
{{medline-entry
|title=Atrial arrhythmia in ageing spontaneously hypertensive rats: unraveling the substrate in hypertension and ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24013508
|abstract=Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR). SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis. COMPARED TO WKY CONTROLS, THE SHR DEMONSTRATED: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006)