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