Credit: Alllex
Using single-nuclei RNA sequencing (snRNA-seq), scientists from Mass General Brigham, SUNY Upstate Medical University, and elsewhere have identified specific brain cell types in the hippocampus that respond best to physical exercise in mouse models of Alzheimer’s disease. The findings help to elucidate the connection between exercise and brain health, and offer fresh insights into potential treatment strategies for people living with Alzheimer’s. Details are provided in a Nature Neuroscience paper titled, “Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing.”
“While we’ve long known that exercise helps protect the brain, we didn’t fully understand which cells were responsible or how it worked at a molecular level,” said Christiane Wrann, DVM, PhD, senior author on the paper and head of the Neuroprotection in Exercise program at Mass General Brigham and Massachusetts General Hospital. The findings reported in the paper provide “a detailed map of how exercise impacts each major cell type in the memory center of the brain in Alzheimer’s disease.”
To understand the neuroprotective effects of exercise on the memory center or hippocampus, the scientists used snRNA-seq to measure gene activity in thousands of individual mouse brain cells. The data was collected after the mice spent time on running wheels, which improved their memory compared to their sedentary counterparts.
The analysis showed that “exercise restored the transcriptional profiles of a proportion of AD-dysregulated genes in a cell type-specific manner,” according to the paper. Specifically, physical movement changed activity in disease-associated microglia and in a specific type of neurovascular-associated astrocyte—these are cells that are associated with blood vessels in the brain. In these cells, the “transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons,” the researchers wrote. Additionally, their analysis revealed that Atpif1, a gene that plays a role in metabolism, is an important regulator in the process of creating new neurons in the brain.
“This work not only sheds light on how exercise benefits the brain but also uncovers potential cell-specific targets for future Alzheimer’s therapies,” said Nathan Tucker, PhD, co-senior author on the study and a biostatistician at SUNY Upstate Medical University. The team has since validated their discoveries in mice in a large snRNA-seq dataset that was generated from brain tissue from Alzheimer’s patients. “Our study offers a valuable resource for the scientific community investigating Alzheimer’s prevention and treatment.”
