Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing

Joana F da Rocha^#¹, Michelle L Lance^#^{2

3}, Renhao Luo^{1

4}, Pius Schlachter^{1

5}, Luis Moreira¹, Mohamed Ariff Iqbal¹, Paula Kuhn¹, Robert S Gardner^{2

3}, Sophia Valaris¹, Mohammad R Islam¹, Gabriele M Gassner^{1

6}, Sofia Mazuera¹, Kaela Healy¹, Sanjana Shastri¹, Nathaniel B Hibbert¹, Kristen V Moran-Figueroa¹, Erin B Haley¹, Ryan D Pfeiffer², Sema Aygar⁷, Ksenia V Kastanenka⁷, Logan Brase⁸, Oscar Harari⁹, Bruno A Benitez¹⁰, Nathan R Tucker^{2

3

11

12}, Christiane D Wrann^{13

14}

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Masonic Medical Research Institute, Utica, NY, USA.
³ Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁵ Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.
⁶ Kiel University Faculty of Medicine, Kiel, Germany.
⁷ Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁸ Department of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
⁹ Department of Neurology, Division of Neurogenetics, The Ohio State University, Columbus, OH, USA.
¹⁰ Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Brookline, MA, USA.
¹¹ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
¹³ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. cwrann@mgh.harvard.edu.
¹⁴ McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA. cwrann@mgh.harvard.edu.

^# Contributed equally.

PMID: 40506544
DOI: 10.1038/s41593-025-01971-w

Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing

Joana F da Rocha et al. Nat Neurosci. 2025 Jul.

. 2025 Jul;28(7):1546-1561.

doi: 10.1038/s41593-025-01971-w. Epub 2025 Jun 12.

Authors

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Masonic Medical Research Institute, Utica, NY, USA.
³ Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
⁴ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁵ Institute of Anatomy and Cell Biology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.
⁶ Kiel University Faculty of Medicine, Kiel, Germany.
⁷ Department of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁸ Department of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.
⁹ Department of Neurology, Division of Neurogenetics, The Ohio State University, Columbus, OH, USA.
¹⁰ Department of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Brookline, MA, USA.
¹¹ Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA.
¹³ Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. cwrann@mgh.harvard.edu.
¹⁴ McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, USA. cwrann@mgh.harvard.edu.

^# Contributed equally.

PMID: 40506544
DOI: 10.1038/s41593-025-01971-w

Abstract

Exercise's protective effects in Alzheimer's disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise restored the transcriptional profiles of a proportion of AD-dysregulated genes in a cell type-specific manner. We identified a neurovascular-associated astrocyte subpopulation, the abundance of which was reduced in AD, whereas its gene expression signature was induced with exercise. Exercise also enhanced the gene expression profile of disease-associated microglia. Oligodendrocyte progenitor cells were the cell type with the highest proportion of dysregulated genes recovered by exercise. Last, we validated our key findings in a human AD snRNA-seq dataset. Together, these data present a comprehensive resource for understanding the molecular mediators of neuroprotection by exercise in AD.

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Conflict of interest statement

Competing interests: C.D.W. is an academic co-founder and consultant for Aevum Therapeutics and 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. Her interests were reviewed and are managed by the MGH and Mass General Brigham in accordance with their conflict-of-interest policies. The other authors declare no competing interests.

References

1. Buchman, A. S. et al. Total daily physical activity and the risk of AD and cognitive decline in older adults. Neurology 78, 1323–1329 (2012). - PMC
1. Huuha, A. M. et al. Can exercise training teach us how to treat Alzheimer’s disease? Ageing Res. Rev. 75, 101559 (2022).
1. Adlard, P. A., Perreau, V. M., Pop, V. & Cotman, C. W. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J. Neurosci. 25, 4217–4221 (2005). - PMC
1. Tapia-Rojas, C., Aranguiz, F., Varela-Nallar, L. & Inestrosa, N. C. Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer’s disease. Brain Pathol. 26, 62–74 (2016).
1. Choi, S. H. et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science https://doi.org/10.1126/science.aan8821 (2018).

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Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing

Affiliations

Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases