Summary: Using state-of-the-art single-nucleus RNA sequencing, researchers mapped how physical exercise reshapes gene expression in specific brain cell types in an Alzheimer’s disease model. The study found that voluntary running alters molecular programs in microglia and a newly identified vascular-associated astrocyte population, and pinpointed a metabolic regulator, Atpif1, that appears to promote the formation of new neurons—findings that were supported by analyses of human Alzheimer’s brain tissue.
These results illuminate how exercise protects memory and suggest precise cell-type targets for future Alzheimer’s disease (AD) therapies, including interventions aimed at boosting neurogenesis and modulating neurovascular and immune responses in the hippocampus.
Key Facts:
- Cell-specific response: Exercise produced prominent transcriptional changes in microglia and in a neurovascular-associated astrocyte subpopulation.
- Neurogenesis driver: The metabolic gene Atpif1 emerged as a candidate regulator of newborn neuron production.
- Human relevance: Major transcriptional signatures observed in the mouse model were validated in human Alzheimer’s disease brain datasets.
Source: Mass General
Using advanced single-nucleus RNA sequencing (snRNA-seq) and a widely used preclinical Alzheimer’s model, investigators from Mass General Brigham with collaborators at SUNY Upstate Medical University have identified the specific hippocampal cell types most responsive to exercise.
The full report appears in Nature Neuroscience. The study focuses on the dentate gyrus of the hippocampus, a memory-critical region that is affected early in Alzheimer’s disease. By profiling thousands of individual nuclei, the team dissected how exercise changes molecular programs across neurons and glial subtypes in this neurogenic niche.
“Although epidemiological and experimental data have long shown that exercise protects the brain, the precise cellular mediators and molecular mechanisms remained unclear,” said senior author Christiane D. Wrann, DVM, PhD, 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. “This work provides a detailed map of exercise-induced transcriptional changes in each major cell type within the dentate gyrus in an Alzheimer’s model.”
The researchers gave APP/PS1 transgenic AD model mice access to running wheels and compared them with sedentary controls. Voluntary running improved memory performance in the exercised mice. snRNA-seq of the dentate gyrus then revealed that exercise drives distinct transcriptomic responses depending on genotype and cell type, with the most pronounced effects observed in immature neurons.
Notably, exercise induced transcriptional shifts in disease-associated microglia and in a neurovascular-associated astrocyte (NVA) subpopulation identified by the team. These NVA astrocytes, which associate closely with blood vessels, were found to be reduced in abundance in AD mice but showed an exercise-induced gene expression signature consistent with restored or enhanced function.
Oligodendrocyte progenitor cells (OPCs) were another cell class in which a high proportion of AD-dysregulated genes were recovered by exercise. Together, the results point to coordinated effects of physical activity on immune, vascular, progenitor, and neuronal compartments within the hippocampal neurogenic zone.
The investigators also identified the metabolic gene Atpif1 as an important regulator linked to the formation of new neurons following exercise. Experimental modulation of genes highlighted by the snRNA-seq analysis altered the behavior of newborn neurons, supporting the functional relevance of the molecular targets discovered.
Lead author Joana Da Rocha, PhD, a postdoctoral fellow in Dr. Wrann’s lab, emphasized the translational potential: “Modulating newborn neurons through the gene targets we identified underscores the promise of leveraging exercise-mimicking mechanisms to protect cognition in Alzheimer’s disease.”
To confirm human relevance, the team validated key signatures in a large human Alzheimer’s disease snRNA-seq dataset and observed consistent patterns, strengthening the case that exercise-responsive pathways discovered in mice translate to human brain biology.
“By revealing cell-specific molecular responses to exercise, this study uncovers candidate targets for precision therapies aimed at Alzheimer’s prevention and treatment,” said Nathan Tucker, a biostatistician at SUNY Upstate Medical University and co-senior author. “We hope this resource will accelerate research into how lifestyle factors like physical activity can be harnessed to protect brain health.”
Authorship: In addition to da Rocha and Wrann, Mass General Brigham contributors 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: Dr. Wrann is an academic co-founder and consultant for Aevum Therapeutics and has a financial interest in the company, which is developing therapeutics that aim to harness exercise-associated molecular mechanisms to treat neurodegenerative and neuromuscular disorders. Her interests have been reviewed and are managed by Massachusetts General Hospital and Mass General Brigham according to institutional conflict-of-interest policies.
Funding: This research was supported in part by multiple National Institutes of Health grants (NS117694, AG062904, AG064580, AG072054, HL140187, AG066171, AG057777, AG072464, NS118146, NS127211) and by funding from Cure Alzheimer’s Fund, the Alzheimer Association Research Grant, the SPARC Award from the McCance Center for Brain Health, the Hassenfeld Clinical Scholar Award, Claflin Distinguished Scholar Award, BIDMC Translational Research Hub Spark Grant, Massachusetts General Hospital Fund for Medical Discovery, ADDF-Harrington Scholar Award, and the Archer Foundation.
About this genetics, exercise, and Alzheimer’s disease research news
Author: Brandon Chase
Source: Mass General
Contact: Brandon Chase – Mass General
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with RNA-single-nucleus sequencing” by Christiane D. Wrann et al., Nature Neuroscience. DOI: 10.1038/s41593-025-01971-w
Abstract
Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with RNA-single-nucleus sequencing
Exercise provides well-established protection against Alzheimer’s disease, yet the cell-specific contributions to this benefit have been incompletely defined. Using single-nucleus RNA sequencing, the study examined responses to voluntary running within the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice.
Transcriptomic responses to exercise differed between wild-type and AD mice and were most pronounced in immature neurons. Exercise restored transcriptional profiles of a subset of AD-dysregulated genes in a cell-type-specific manner, induced the gene-expression signature of a neurovascular-associated astrocyte subpopulation that is depleted in AD, and enhanced the profile of disease-associated microglia. Oligodendrocyte progenitor cells showed the highest proportion of dysregulated genes recovered by exercise. Key findings were validated in a human AD snRNA-seq dataset. Collectively, these data create a comprehensive resource to understand molecular mediators of exercise-induced neuroprotection in Alzheimer’s disease.