Using advanced single-nuclei RNA sequencing (snRNA-seq) and a widely used preclinical model for Alzheimer's disease, researchers from Mass General Brigham and collaborators at SUNY Upstate Medical University have identified specific brain cell types that responded most to exercise. These findings, which were validated in samples from people, shed light on the connection between exercise and brain health and point to future drug targets. Results are published in Nature Neuroscience .
"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 senior author Christiane D. Wrann, DVM, PhD, a neuroscientist and leader 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. "Now, we have a detailed map of how exercise impacts each major cell type in the memory center of the brain in Alzheimer's disease."
The study focused on a part of the hippocampus—a critical region for memory and learning that is damaged early in Alzheimer's disease. The research team leveraged single-nuclei RNA sequencing, a relatively new technologies that allow researchers to look at activity at the molecular level in single cells for an in-depth understanding of diseases like Alzheimer's.
The researchers exercised a common mouse model for Alzheimer's disease using running wheels, which improved their memory compared to the sedentary counterparts. They then analyzed gene activity across thousands of individual brain cells, finding that exercise changed activity both in microglia, a disease-associated population of brain cells, and in a specific type of neurovascular-associated astrocyte (NVA), newly discovered by the team, which are cells associated with blood vessels in the brain. Furthermore, the scientist identified the metabolic gene Atpif1 as an important regulator to create new neurons in the brain. "That we were able to modulate newborn neurons using our new target genes set underscores the promise our study," said lead author Joana Da Rocha, PhD, a postdoctoral fellow working in Dr. Wrann's lab.
To ensure the findings were relevant to humans, the team validated their discoveries in a large dataset of human Alzheimer's brain tissue, finding striking similarities.
"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, a biostatistician at SUNY Upstate Medical University and co-senior of the study. "Our study offers a valuable resource for the scientific community investigating Alzheimer's prevention and treatment."
Authorship: In addition to da Rocha and Wrann, Mass General Brigham authors include Renhao Luo, Pius Schlachter, Luis Moreira, Mohamed Ariff Iqbal, Paula Kuhn, Sophia Valaris, Mohammad R. Islam, Gabriele M. Gassner, Sofia Mazuera, Kaela Healy, Sanjana Shastri, Nathaniel B. Hibbert, Kristen V. Moran-Figueroa, Erin B. Haley, Sema Aygar, and Ksenia V. Kastanenka. Additional authors include Michelle L. Lance, Robert S. Gardner, Ryan D. Pfeiffer, Logan Brase, Oscar Harari, Bruno A. Benitez, and Nathan R. Tucker.
Disclosures: Wrann is an academic co-founder and consultant for Aevum Therapeutics. Wrann has a financial interest in Aevum Therapeutics, a company developing drugs that harness the protective molecular mechanisms of exercise to treat neurodegenerative and neuromuscular disorders. Wrann's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies.
Funding: This study was funded in part by the National Institutes of Health (NS117694, AG062904, AG064580, AG072054, HL140187, AG066171, AG057777, AG072464, NS118146, NS127211), Cure Alzheimer's Fund, Alzheimer Association Research Grant, SPARC Award from the McCance Center for Brain Health, Hassenfeld Clinical Scholar Award, Claflin Distinguished Scholar Award, BIDMC 2023 Translational Research Hub Spark Grant Award, Massachusetts General Hospital Fund for Medical Discovery (2024A022508), ADDF-Harrington
Scholar Award, and Archer Foundation Research Scientist.
Paper cited: da Rocha JF et al. "Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with RNA-single-nucleus sequencing" Nature Neuroscience DOI: 10.1038/s41593-025-01971-w
