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

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. Hypothalamus from mice with SRC-1 gene deletion and control mice were isolated, RNA extracted, and RNA-sequencing was performed.

与衰老相关的痴呆（包括阿尔茨海默病，Alzheimer’s Disease, AD）的致病机制迄今尚未阐明。本研究通过RNA测序分析（RNA-Seq）发现，类固醇受体辅激活因子-1（SRC-1）的缺失会导致与包括阿尔茨海默病在内的神经退行性疾病密切相关的基因表达特征发生改变。与既往研究结果一致，本研究证实SRC-1缺失会削弱海马CA1神经元的神经可塑性。认知行为实验结果显示，SRC-1敲除（SRC-1-KO）小鼠与人源化SRC-1突变（SRC-1L1376P）小鼠在仅6月龄时即出现情境记忆损伤的早期症状；而野生型小鼠通常在18月龄时才会出现衰老相关的记忆衰退。上述结果表明SRC-1对衰老相关的认知衰退具有保护作用。为进一步探究其分子机制，本研究重新分析了公开获取的年轻及衰老小鼠大脑的空间RNA测序（spatial RNA-Seq）数据，发现衰老小鼠下丘脑与海马体中，SRC-1与阿尔茨海默病相关基因S100钙结合蛋白A6（S100A6）的表达均同步下调。值得注意的是，本研究的RNA-Seq数据显示，S100A6是SRC-1-KO小鼠中受抑制最显著的基因之一。本研究还确定S100A6与S100A11为SRC-1的下游靶点，同时也是潜在的阿尔茨海默病相关基因，为阐明SRC-1抵御衰老相关认知衰退的保护作用提供了全新视角。本研究分离了SRC-1基因敲除小鼠与对照小鼠的下丘脑组织，提取RNA并开展了RNA测序。