Duncan NRI Faculty and Staff Publications

Language

English

Publication Date

8-27-2025

Journal

Aging

DOI

10.18632/aging.206311

PMID

40882002

PMCID

PMC12422791

PubMedCentral® Posted Date

8-27-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Nuclear Receptor Coactivator 1, Cognitive Dysfunction, Mice, Aging, Mice, Knockout, S100 Calcium Binding Protein A6, Humans, Male, Neuronal Plasticity, aging, dementia, SRC-1, S100A6

Published Open-Access

yes

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