Cognition Aging
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB90935 | ENA |
REPOSITORIES: ENA
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Project description:Aging leads to a progressive deterioration in brain function, which will eventually result in cognitive decline and can develop into a dementia. The mechanisms underlying pathological cognitive decline in aging are still poorly understood. The peripheral immune system, as well as the meningeal lymphatic vasculature and the immune cells residing in the brain and meninges, are all affected by aging. Moreover, recent studies have linked the dysfunction of the meningeal lymphatic system and peripheral immunity to accelerated brain aging. We hypothesized that an age-related reduction in CCR7-dependent immune cell egress through the lymphatic vasculature mediates some aspects of aging-associated brain dysfunction, leading to cognitive decline and potentially exacerbating neurodegenerative diseases. Here, we report a reduction in CCR7 expression by meningeal T cells in aged mice and its associated increase in meningeal T-regulatory cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to cognitive impairment. Interestingly, CCR7-deficient mice also presented impaired brain glymphatic function and showed increased amyloid beta (A) deposition when crossed with the 5xFAD transgenic mouse model of Alzheimer’s disease (AD). These results show that the aging-associated decrease in CCR7 expression impacts meningeal immunity, affects different aspects of brain function and exacerbates brain A pathology, highlighting its potential as a pathogenic mechanism for cognitive decline in aging and AD.
2021-03-22 | GSE163725 | GEO
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.
2011-12-23 | E-GEOD-25009 | biostudies-arrayexpress
Project description:Platelet factors regulate wound healing and also signal from the blood to the brain. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here, we show that systemic platelet factor 4 (PF4) modulates cognition and its molecular signature. Klotho, a longevity and cognition-enhancing protein, acutely activated platelets and increased circulating platelet factors, most robustly platelet factor 4 (PF4). To directly test PF4 effects on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In aging mice, PF4 restored cognitive deficits and rejuvenated a molecular signature of cognition in the aging hippocampus. Augmenting platelet factors such as PF4, a possible messenger of klotho, may enhance cognition in the young brain and rejuvenate cognitive deficits in the aging brain.
2023-06-24 | GSE171929 | GEO
Project description:The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with human aging and AD. Overall, the present study shows that in addition to the widely recognized astrocytic EAAT2, neuronal EAAT2 plays a role in hippocampus-dependent memory. Furthermore, the gene expression profiles associated with astrocytic and neuronal EAAT2 deletion are substantially different, with the former associated with inflammation and synaptic function similar to changes observed in human AD and gene expression changes associated with inflammation similar to the aging human brain.
2021-03-18 | GSE169083 | GEO
Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases.
2014-10-01 | GSE56452 | GEO
Project description:Cognitive decline is a common occurrence of the natural aging process in animals, and studying age-related changes in gene expression in the brain might shed light on disrupted molecular pathways that play a role in this decline. The fruit fly is a useful neurobiological model for studying aging due to its short generational time and relatively small brain size. We investigated age-dependent changes in the Drosophila melanogaster whole-brain transcriptome by comparing 5-, 20-, 30- and 40-day-old flies of both sexes. We used RNA-Sequencing of dissected brain samples followed by differential expression, temporal clustering, co-expression network and gene ontology enrichment analyses. Our study provides the first transcriptome profile of aging brains from fruit flies of both sexes, and it will serve as an important resource for those who study aging and cognitive decline in this model.
2019-05-17 | GSE107049 | GEO
Project description:Cognitive decline in aging is a major issue, causing both personal and economic hardship in an increasingly aging society. There are several known individual misfolded proteins that cause issues with age, such as amyloid beta and alpha synuclein. However, many studies have found that the proteostasis network, which works to keep proteins properly folded, is impaired with age, suggesting that there may be more global protein structural changes. We used limited-proteolysis mass spectrometry (LiP-MS) to investigate protein structural changes proteome-wide in a rodent model of aging. We compared hippocampi from aged rodents with normal cognition (aged unimpaired, AU) to hippocampi from aged rodents with impaired cognition (aged impaired, AI). We identified several hundred proteins as Cognition-Associated Structural Changes (CASCs), which are structurally different between the AU and AI populations. We found correlations between these trends and those of protein refoldability, a separate measure of how well a protein can independently refold to its native state after complete denaturation. CASCs were enriched with nonrefoldable proteins. Potential confounding factors of our study such as LiP reproducibility and post-translational modifications were assessed. Searches for oxidation and phosphorylation did not yield significant differences between AU and AI samples within each hippocampal region. Our study overall suggests that neuronal protein structural changes are global in nature and are more often intrinsically nonrefoldable, which may partially explain their susceptibility to structural changes due to proteostasis network breakdown in age.
2025-07-12 | PXD052770 | Pride
Project description:Normal aging process is accompanied by cognitive decline. Studies have shown that the hypothalamus plays an important role in regulating aging and cognition. However, the exact molecular mechanism remains unclear. Therefore, the present study aimed to identify predictors of aging cognitive decline in the hypothalamus. The behavioral experiment was used to identify learning and memory differences between young and old mice. Transcriptome sequencing was performed on the hypothalamus of young and old mice to identify potential genes.Our data provide the related genes ,which may be potential predictors of cognitive function in the elderly population, which will establish an important foundation for us to further explore the molecular mechanism.
2024-07-01 | GSE240365 | GEO
Project description:Age-related cognitive decline in humans is associated with altered physiology of the hippocampus, a region critical for memory consolidation and spatial navigation. While changes in gene expression have been observed in aging brain cells, our understanding of the regulatory mechanisms underlying these changes and their connection to chromatin structure remains limited. To unravel these complexities, we have applied a comprehensive multi-omics approach, integrating single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D chromatin architecture data obtained from the hippocampi of 40 neurotypical human donors spanning the adult lifespan. We observed a striking loss of astrocytes, oligodendrocyte precursor cells, and endothelial cells during aging. In particular, we observed a substantial decline in the subset of astrocytes that play a role in maintaining and regulating synaptic transmission. In addition, microglia undergo a dramatic switch from a predominantly homeostatic state to an epigenetically primed inflammatory state that coincides with reprogramming of their DNA methylomes and activation of endogenous retrotransposons. In the aged cells, we detected erosion of the 3D genome architecture, where local chromatin domains are diminished and trans-chromosomal interactions are strengthened. Importantly, age-related changes in chromatin folding have high correspondence with the transcriptome and epigenome in multiple cell types. Our data identifies age-associated changes in cell types/states and gene regulatory features that provide insight into the loss of synapses and cognitive decline that occurs in the human brain during aging.
2024-12-05 | GSE278576 | GEO