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A protective role of SRC-1 against aging associated cognitive decline

ABSTRACT: The mechanisms underlying dementia, including Alzheimer’s Disease (AD), associated with aging remain elusive. Our RNA sequencing analysis (RNA-Seq) revealed that the loss of steroid receptor coactivator-1 (SRC-1) leads to alterations in gene expression signatures that are commonly associated with neurodegenerative diseases, including AD. Consistent with previous findings, our research indicates that SRC-1 deficiency diminishes the neural plasticity of the hippocampal CA1 neurons. Cognitive behavior tests demonstrate that both SRC-1-KO mice and mice with a humanized SRC-1 mutation (SRC-1L1376P) displayed early signs of contextual memory impairment at just 6 months of age, in contrast to the typical aging-associated memory decline observed in wild type mice at 18 months of age. These results suggest a protective role of SRC1 against aging-associated cognitive decline. To further explore the molecular mechanism, we reanalyzed publicly available spatial RNA-Seq data of both young and aged mouse brains. We found a synchronous decline in SRC-1 and S100 calcium-binding protein A6 (S100A6), an AD associated gene, in both the hypothalamus and hippocampus of aged brain. Notably, our RNA-Seq data highlighted S100A6 as one of the most profoundly inhibited genes in SRC-1-KO mice. We also identified S100A6 and S100A11 as potential AD-associated genes that are downstream targets of SRC-1, offering novel perspectives on the protective role of SRC1 against cognitive decline due to aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE278158 | GEO | 2025/09/17

REPOSITORIES: GEO

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Project description:Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer’s disease (AD), however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investigate the relationship between physical activity levels and gene expression patterns in the cognitively-intact aged human hippocampus. In parallel, hippocampal gene expression patterns associated with Aging and AD were assessed using publicly available microarray data profiling hippocampus from young (20-59 yrs), cognitively-intact aging (73-95 yrs) and age-matched AD cases. To identify “anti-Aging/AD” transcription patterns associated with physical activity, probesets significantly associated with both physical activity and Aging/AD were identified and their directions of expression change in each condition were compared. Remarkably, of the 2138 probesets significant in both datasets, nearly 95% showed opposite transcription patterns with physical activity compared to Aging/AD. The majority (>70%) of these anti-Aging/AD genes showed increased expression with physical activity and decreased expression in Aging/AD. Enrichment analysis of the anti-Aging/AD genes showing increased expression in association with physical activity revealed strong overrepresentation of mitochondrial energy production and synaptic function, along with axonal function and myelin integrity. Synaptic genes were notably enriched for synaptic vesicle priming, release and recycling, glutamate and GABA signaling and synaptic spine plasticity. Anti-Aging/AD genes showing decreased expression in association with physical activity were enriched for transcription-related function. These data suggest that physical activity preserves a more youthful profile in the hippocampus across multiple biological processes, providing a potential molecular foundation for how physical activity can delay age- and AD-related decline of hippocampal function.

Project description:The decline of cognitive function is a feature of normal human aging and is exacerbated in AlzheimerM-bM-^@M-^Ys disease (AD). DNA repair declines in brain cells during normal aging and even more so in AD. Here we show that experimental reduction in levels of the base excision repair enzyme, DNA polymerase M-NM-2 (Polb) renders neurons vulnerable to age-related dysfunction and degeneration in a mouse model of AD. Whereas 3xTgAD mice exhibit age-related extracellular amyloid b-peptide (Ab) accumulation and cognitive deficits, but no neuronal death, 3xTg/Polb+/- mice accumulates intracellular Ab and neurons die in the hippocampus and cerebral cortex. The DNA repair-deficient 3xTgAD mice exhibited increased DNA strand breaks and apoptotic caspase activation with loss of hippocampal volume, and impaired synaptic plasticity and memory retention. Molecular profiling revealed remarkable similarities in gene expression alterations in brain cells of AD patients and 3xTgAD/Polb+/- mice including multiple abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in oxidative DNA damage processing is sufficient to render neurons vulnerable to AD-related pathogenic molecular and cellular alterations that result in the dysfunction and death of neurons, and associated cognitive deficits. 4 mouse strains were used in these experiments, the 3xTgAD and Pol M-NM-2 (+/-) mice were bred at the National Institute on Aging (Baltimore, Maryland). The original line 3xTgAD line was generated as described previously (Oddo, et. al 2003) and possess APPswe, PS1M146V, and tauP301L mutations. DNA polymerase beta heterozygous mice, Pol M-NM-2 (+/-), were crossed with the 3xTgAD mice to generate a 3xTgAD/Pol M-NM-2 (+/-) mouse. The Wt strain is C57Bl/6. At 20 months of age these mice were euthanized by cervical dislocation, the brain removed from the skull and dissected into regions of interest, the prefrontal cortex was used for the microarray studies.

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A protective role of SRC-1 against aging associated cognitive decline

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