In a groundbreaking study combining cutting-edge genetic tools with an established model of Alzheimer’s disease, researchers from Mass General Brigham, in collaboration with colleagues at SUNY Upstate Medical University, have pinpointed specific brain cell types most responsive to physical exercise. Employing advanced single-nuclei RNA sequencing (snRNA-seq), the team examined the molecular effects of exercise on individual brain cells, illuminating the cellular mechanisms that link physical activity to improved brain health. Importantly, these findings were validated using brain tissue from human subjects, reinforcing their clinical relevance. The complete study is published in Nature Neuroscience.
Although the protective effects of exercise on cognitive function have long been recognised, the precise cellular and molecular underpinnings remained elusive. Senior author Dr Christiane D. Wrann, DVM, PhD, a neuroscientist and head of the Program in Neuroprotection in Exercise at the Mass General Brigham Heart and Vascular Institute and the McCance Center for Brain Health at Massachusetts General Hospital, explained the significance of the new findings. “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,” she noted. “Now, we have a detailed map of how exercise impacts each major cell type in the memory centre of the brain in Alzheimer’s disease.”
The research concentrated on the hippocampus, a critical brain region associated with memory and learning that is notably vulnerable to early degeneration in Alzheimer’s disease. Utilising the snRNA-seq technology—an innovation that enables researchers to analyse gene expression at the single-cell level—the team was able to dissect the distinct responses of various brain cell types to physical activity. This granular approach allows for a much more precise understanding of the disease’s pathology and the benefits of exercise.
In the experimental phase, the team used a widely studied mouse model of Alzheimer’s disease, providing the animals access to running wheels. Those who engaged in voluntary running showed marked improvements in memory function compared to their sedentary counterparts. When the researchers analysed the brains of these exercised mice, they discovered exercise-induced changes in gene expression across thousands of individual cells. Particularly notable were alterations in microglia—a type of immune cell in the brain implicated in neurodegenerative disease—and a newly identified subset of astrocytes known as neurovascular-associated astrocytes (NVAs), which interact closely with the brain’s blood vessels.
Among the most intriguing molecular findings was identifying the gene Atpif1, a metabolic regulator that appears to play a key role in neurogenesis—the process by which new neurons are generated. The team found that modulation of this gene influenced the production of new brain cells, suggesting it could be a promising target for therapeutic intervention. Dr Joana Da Rocha, a postdoctoral researcher in Dr Wrann’s laboratory and lead author of the study, highlighted the importance of this discovery. “That we were able to modulate newborn neurons using our new target genes underscores the promise of our study,” she said, pointing to the potential for these findings to guide future drug development.
To confirm that their observations in mice applied to humans, the researchers examined a large dataset of human brain tissue from individuals diagnosed with Alzheimer’s. Their analysis revealed strong parallels between the cellular changes observed in the exercised mice and those found in the human samples, reinforcing the results’ translatability. Co-senior author Dr Nathan Tucker, a biostatistician at SUNY Upstate Medical University, underscored the broader implications of the work: “This study not only sheds light on how exercise benefits the brain but also uncovers potential cell-specific targets for future Alzheimer’s therapies. Our findings provide a valuable resource for the scientific community focused on Alzheimer’s prevention and treatment.”
In sum, this research not only maps the beneficial impact of physical activity at the single-cell level but also opens the door to new lines of inquiry into how lifestyle interventions can influence the course of neurodegenerative disease. By bridging the gap between animal models and human pathology, the study offers compelling evidence that physical activity could one day inform precision medicine approaches to combat Alzheimer’s disease, both as a preventive measure and as a foundation for targeted therapeutics.
More information: Joana Da Rocha et al, Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing, Nature Neuroscience. DOI: 10.1038/s41593-025-01971-w
Journal information: Nature Neuroscience Provided by Mass General Brigham
