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<p>Exercise’s protective effects in Alzheimer’s disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise restored the transcriptional profiles of a proportion of AD-dysregulated genes in a cell type-specific manner. We identified a neurovascular-associated astrocyte subpopulation, the abundance of which was reduced in AD, whereas its gene expression signature was induced with exercise. Exercise also enhanced the gene expression profile of disease-associated microglia. Oligodendrocyte progenitor cells were the cell type with the highest proportion of dysregulated genes recovered by exercise. Last, we validated our key findings in a human AD snRNA-seq dataset. Together, these data present a comprehensive resource for understanding the molecular mediators of neuroprotection by exercise in AD.</p>

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Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing

  • 期刊论文

  • 发表日期：

    2025年6月12日

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  • Joana F. da Rocha,
  • Michelle L. Lance,
  • Renhao Luo,
  • Pius Schlachter,
  • Luis Moreira,
  • Mohamed Ariff Iqbal,
  • Paula Kuhn,
  • Robert S. Gardner,
  • Sophia Valaris,
  • Mohammad R. Islam,
  • Gabriele M. Gassner,
  • Sofia Mazuera,
  • Kaela Healy,
  • Sanjana Shastri,
  • Nathaniel B. Hibbert,
  • Kristen V. Moran-Figueroa,
  • Erin B. Haley,
  • Ryan D. Pfeiffer,
  • Sema Aygar,
  • Ksenia V. Kastanenka,
  • Logan Brase,
  • Oscar Harari,
  • Bruno A. Benitez,
  • Nathan R. Tucker,
  • Christiane D. Wrann

摘要

Exercise’s protective effects in Alzheimer’s disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise restored the transcriptional profiles of a proportion of AD-dysregulated genes in a cell type-specific manner. We identified a neurovascular-associated astrocyte subpopulation, the abundance of which was reduced in AD, whereas its gene expression signature was induced with exercise. Exercise also enhanced the gene expression profile of disease-associated microglia. Oligodendrocyte progenitor cells were the cell type with the highest proportion of dysregulated genes recovered by exercise. Last, we validated our key findings in a human AD snRNA-seq dataset. Together, these data present a comprehensive resource for understanding the molecular mediators of neuroprotection by exercise in AD.