单核RNA测序揭示阿尔茨海默病小鼠齿状回的保护性运动反应，这一成果由麻省总医院和哈佛医学院Christiane D. Wrann研究组经过不懈努力而取得。该研究于2025年6月12日发表于国际一流学术期刊《自然—神经科学》杂志上。

本研究以单核RNA测序（snRNA-seq）为主题，分析了APP/PS1转基因雄性AD模型小鼠海马齿状回神经源性干细胞生态位对运动（自由轮跑）的反应。运动的转录组反应在野生型和AD小鼠之间是不同的，并且在未成熟的神经元中最为突出。运动以细胞类型特异性的方式恢复了一部分AD失调基因的转录谱。课题组人员发现了一个与神经血管相关的星形胶质细胞亚群，其丰度在阿尔茨海默病中降低，而其基因表达特征是通过运动诱导的。运动还增强了疾病相关小胶质细胞的基因表达谱。少突胶质祖细胞是运动恢复失调基因比例最高的细胞类型。最后，该研究组在人类AD snRNA-seq数据集中验证了他们的关键发现。总之，这些数据为理解运动对阿尔茨海默病的神经保护的分子介质提供了全面的抵抗。

据悉，运动对阿尔茨海默病（AD）的保护作用已得到充分认识，但细胞特异性对这一现象的贡献尚不清楚。

附：英文原文

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

Author: 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.

Issue&Volume: 2025-06-12

Abstract: 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.

DOI: 10.1038/s41593-025-01971-w

Source: https://www.nature.com/articles/s41593-025-01971-w