ArticleNature neuroscience2025
Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing.
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Article in Nature neuroscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16citing papers in PubMed
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Who cites it
16 citing papers in PubMed.
- Astrocytic apelin mediates cortical neuronal function and prevents anxiety-like behaviors in mice.Acta pharmacologica Sinica · 2026Article
- Role Shift of Glial Cells from Physiology to Pathology in Alzheimer's Disease: The Regulatory Impact of Exercise.Neuroscience bulletin · 2026Review
- A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19.bioRxiv : the preprint server for biology · 2026Article
- Exercise mimetics: molecular mechanisms, biological and therapeutic effects.Molecular biomedicine · 2026Review
- Irisin promotes selective changes in hippocampal mitochondrial metabolism in mice.Biochemistry and biophysics reports · 2026Article
- Cell-state mapping reveals a reversible neuroblast accumulation in the aging mouse hippocampus.bioRxiv : the preprint server for biology · 2026Article
- Article
- Exercise Reprograms the Spatial Function of Phosphoglycerate Dehydrogenase of a Pathogenic Nuclear Transcription Factor (PHGDH): A Narrative Review.Metabolites · 2026Review
- Ketone body β-hydroxybutyrate restores neuronal Tau proteostasis via ketolysis-independent mechanism.bioRxiv : the preprint server for biology · 2026Article
- Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING Signalling, in Aged Hippocampus.Journal of extracellular vesicles · 2026Article
- Exploring the gut-brain axis: dietary influences on Alzheimer's disease pathogenesis.Frontiers in microbiomes · 2026Review
- Therapeutic potential of exerkines in neurodegenerative and mental disorders: a narrative review.Frontiers in physiology · 2026Review
- The Influence of Lifestyle on Cognitive Function and Quality of Life in People with Dementia.Neuropsychiatric disease and treatment · 2026Article
- Exercise-conditioned extracellular vesicles in Alzheimer's disease: a multi-organ signaling network linking peripheral adaptation to brain pathology.Frontiers in immunology · 2026Review
- Exercise training-induced benefits for Alzheimer's disease are associated with modulation of the BDNF-TrkB signaling complex.Scientific reports · 2025Article
- Exercise mitigates Alzheimer's disease by targeting ferroptosis driven by cellular senescence.Frontiers in cell and developmental biology · 2025Review
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Authors and funding
25 authors.
Joana F da Rocha *Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-2496-4061
Michelle L Lance *Masonic Medical Research Institute, Utica, NY, USA.
Renhao LuoCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3489-1799
Pius SchlachterCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0009-3686-3952
Luis MoreiraCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Mohamed Ariff IqbalCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-5094-0717
Paula KuhnCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Robert S GardnerMasonic Medical Research Institute, Utica, NY, USA.
Sophia ValarisCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Mohammad R IslamCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Gabriele M GassnerCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0002-0386-5328
Sofia MazueraCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0009-4430-6793
Kaela HealyCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Sanjana ShastriCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0004-8245-8249
Nathaniel B HibbertCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Kristen V Moran-FigueroaCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Erin B HaleyCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Ryan D PfeifferMasonic Medical Research Institute, Utica, NY, USA.
Sema AygarDepartment of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.ORCID http://orcid.org/0000-0001-8112-0343
Ksenia V KastanenkaDepartment of Neurology, MassGeneral Institute of Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Logan BraseDepartment of Psychiatry, Washington University, Saint Louis, St. Louis, MO, USA.ORCID http://orcid.org/0000-0002-7175-3208
Oscar HarariDepartment of Neurology, Division of Neurogenetics, The Ohio State University, Columbus, OH, USA.ORCID http://orcid.org/0000-0002-2635-6975
Bruno A BenitezDepartment of Neurology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Brookline, MA, USA.ORCID http://orcid.org/0000-0002-2699-3878
Nathan R TuckerMasonic Medical Research Institute, Utica, NY, USA.
Christiane D WrannCardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. cwrann@mgh.harvard.edu.ORCID http://orcid.org/0000-0001-6066-8799
Funding
Investigating the Functional Impact of AD Risk Genes on Neuro-Vascular InteractionsU01AG072464 · NIA · REGENERATIVE RESEARCH FOUNDATION · PI HARARI, OSCAR, KAMPMANN, MARTIN · 2021 to 2025
$8.7MMENDELIAN RANDOMIZATION FOR UNBIAS BIOMARKER DISCOVERY FOR AD AND OTHER COMPLEX TRAITSR01AG057777 · NIA · WASHINGTON UNIVERSITY · PI HARARI, OSCAR · 2018 to 2022
$4.1MMulti-tissue High-throughput Proteomic and Genomic Study in Parkinson's DiseaseR01NS118146 · NINDS · WASHINGTON UNIVERSITY · PI BENITEZ, BRUNO · 2020 to 2025
$3.2MElucidating circuit disruptions in Alzheimer's diseaseR01AG066171 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI KASTANENKA, KSENIA V. · 2020 to 2024
$2.9MFNDC5/irisin as a Molecular Mediator of Exercise Benefits in Cognitive FunctionR01NS117694 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI Christiane D. Wrann · 2022 to 2026
$2.5MHuman iPSC model of Cerebro-Vascular Interactions in ADRDR61NS138655 · NINDS · REGENERATIVE RESEARCH FOUNDATION · PI TEMPLE, SALLY · 2024 to 2024
$1.9MDefining the functional variation underlying atrial fibrillation riskK01HL140187 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI TUCKER, NATHAN R · 2018 to 2022
$858kExploring irisin as a novel target for Alzheimers DiseaseR56AG072054 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI CHOI, SE HOON, WRANN, CHRISTIANE D. · 2022 to 2022
$785kMolecular mechanisms of exercise benefits in synapse plasticity and cognitionR00NS087096 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI WRANN, CHRISTIANE D. · 2017 to 2019
$745kDissecting the molecular mediators of the neuroprotective effects of exercise in Alzheimer's DiseaseR56AG064580 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI WRANN, CHRISTIANE D. · 2019 to 2019
$590kThe role of CSPalpha in Adult onset neuronal Lipofuscinosis pathogenesisR21NS127211 · NINDS · BETH ISRAEL DEACONESS MEDICAL CENTER · PI BENITEZ, BRUNO A. · 2022 to 2022
$491kExploring irisin as a novel target for Alzheimer's DiseaseR21AG062904 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI CHOI, SE HOON, WRANN, CHRISTIANE D. · 2019 to 2020
$462kNHLBI NIH HHS K01 HL140187NIA NIH HHS R01 AG057777NIA NIH HHS R01 AG066171NIA NIH HHS R21 AG062904NIA NIH HHS R56 AG064580NIA NIH HHS R56 AG072054NIA NIH HHS U01 AG072464NINDS NIH HHS R00 NS087096NINDS NIH HHS R01 NS117694NINDS NIH HHS R01 NS118146NINDS NIH HHS R21 NS127211NINDS NIH HHS R61 NS138655U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) HL140187U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS117694U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS118146U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS127211U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG057777U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG062904U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG064580U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG066171U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG072054U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG072464
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.
Indexed as
Alzheimer DiseaseDentate GyrusPhysical Conditioning, AnimalAnimalsDisease Models, AnimalHumansMaleMiceMice, Inbred C57BLMice, TransgenicMicrogliaSequence Analysis, RNATranscriptome
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