Published on: Jun 12, 2025
Using cutting-edge single-nuclei RNA sequencing (snRNA-seq) and a widely accepted preclinical model of Alzheimer’s disease, researchers from Mass General Brigham, in collaboration with SUNY Upstate Medical University, have pinpointed the specific brain cell types that respond most significantly to exercise. Their findings—confirmed using human tissue samples—highlight the powerful link between physical activity and brain health, while also revealing new potential targets for Alzheimer’s treatment. The results were published in Nature Neuroscience.
Although we've known for some time that exercise has protective effects on the brain, the exact cells involved and the underlying molecular mechanisms were unclear,” explained senior author Christiane Wrann, DVM, PhD, neuroscientist and director 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. “With this study, we now have a detailed map showing how exercise affects each major cell type in the brain’s memory center in Alzheimer’s disease.”
The study focused on the hippocampus, a key brain region responsible for memory and learning and one of the earliest affected areas in Alzheimer’s. By using snRNA-seq—a powerful tool that enables scientists to study gene activity at the single-cell level—the team gained deep insights into how exercise influences individual brain cells.
Mice with a genetic model of Alzheimer’s were given access to running wheels, which led to improved memory performance compared to inactive mice. Further analysis revealed that exercise altered gene activity in microglia—immune-related brain cells—and in a newly identified subtype of astrocytes linked to brain blood vessels, called neurovascular-associated astrocytes (NVA). The researchers also highlighted the gene Atpif1 as a key metabolic regulator involved in promoting the formation of new neurons.
“Our ability to stimulate the production of new neurons using this newly identified gene target is a major step forward,” said lead author Joana Da Rocha, PhD, a postdoctoral fellow in Dr. Wrann’s lab.
To confirm the relevance of their findings in humans, the team validated their results using a large dataset of human Alzheimer’s brain tissue, uncovering remarkable parallels.
“This study not only deepens our understanding of how exercise benefits brain health but also identifies cell-specific targets for future Alzheimer’s therapies,” said co-senior author Nathan Tucker, a biostatistician at SUNY Upstate Medical University. “It provides a valuable roadmap for researchers working on Alzheimer’s prevention and treatment.
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