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ABSTRACT

Introduction: Research indicates a strong correlation between obesity and the risk of dementia, both are linked to steroid receptor coactivator-1 (SRC-1), a transcriptional coactivator. Methods: We used RNA sequencing analysis (RNA-Seq) to investigate the transcriptome of SRC-1-KO mice, and identified S100 calcium-binding protein A6 (S100A6), an AD associated gene, as one target of SRC-1. We tested cognitive behaviors in SRC-1-KO mice and mice with a humanized SRC-1 mutation (SRC-1L1376P), and performed promoter luciferase assays on S100A6. Results: Loss of SRC-1 caused alterations in gene signatures that are commonly associated with neurodegenerative diseases, including AD, and diminished the neural plasticity of the hippocampal CA1 neurons. Both SRC-1-KO and SRC-1L1376P mice displayed early signs of contextual memory impairment at 6 months of age. Mechanistically, SRC-1 significantly promoted the expression S100A6. Conclusion: We identified a protective role of SRC1 against aging associated cognitive decline, potentially by promoting the expression of S100A6.

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