June 2025, Nature Neuroscience: Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing

Results of a long-term collaborative effort from the Wrann Lab at Mass General Brigham and the Tucker Lab at SUNY Upstate, highlighting exercise induced protection in Alzheimer's by profiling the murine brain transcriptome at single cell level. We identify key changes in cell type specific responses, including in immature neurons. Small scale validation of targeted candidates also show impact on neuronal survival in in vitro assays. Co-led by Nate and Christiane, with single cell library generation and analysis by Ryan, Michelle, and Bob in the lab.

Abstract from 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.