da Rocha Joana F, Lance Michelle L, Luo Renhao, Schlachter Pius, Moreira Luis, Iqbal Mohamed Ariff, Kuhn Paula, Gardner Robert S, Valaris Sophia, Islam Mohammad R, Gassner Gabriele M, Mazuera Sofia, Healy Kaela, Shastri Sanjana, Hibbert Nathaniel B, Moran-Figueroa Kristen V, Haley Erin B, Pfeiffer Ryan D, Aygar Sema, Kastanenka Ksenia V, Brase Logan, Harari Oscar, Benitez Bruno A, Tucker Nathan R, Wrann Christiane D
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Masonic Medical Research Institute, Utica, NY, USA.
Nat Neurosci. 2025 Jun 12. doi: 10.1038/s41593-025-01971-w.
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.
运动对阿尔茨海默病（AD）的保护作用已得到广泛认可，但细胞特异性对这一现象的贡献仍不清楚。在这里，我们使用单核RNA测序（snRNA-seq）来剖析雄性APP/PS1转基因AD模型小鼠海马齿状回神经源性干细胞微环境对运动（自由轮转跑步）的反应。野生型和AD小鼠对运动的转录组反应不同，且在未成熟神经元中最为显著。运动以细胞类型特异性方式恢复了一部分AD失调基因的转录谱。我们鉴定出一种与神经血管相关的星形胶质细胞亚群，其丰度在AD中降低，而其基因表达特征在运动时被诱导。运动还增强了疾病相关小胶质细胞的基因表达谱。少突胶质细胞祖细胞是运动恢复失调基因比例最高的细胞类型。最后，我们在人类AD snRNA-seq数据集中验证了我们的关键发现。总之，这些数据为理解运动在AD中神经保护的分子介质提供了全面的资源。
