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.
da Rocha, J.F., Lance, M.L., Luo, R. et al. Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing.
Nat Neurosci (2025).
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da Rocha, J.F., Lance, M.L., Luo, R. et al. Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing.
Nat Neurosci (2025). https://doi.org/10.1038/s41593-025-01971-w
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Tags: Alzheimer’s disease researchAPP/PS1 transgenic miceastrocyte subpopulations in exercisedentate gyrus responsesexercise and neuroprotectionimmature neurons and exercisemicroglial gene expression in ADmolecular mediators of exercise benefitsneurogenic stem-cell nicheoligodendrocyte progenitor cell dysregulationsingle-nucleus RNA sequencingtranscriptional profiles in AD
