Regular Running Wards Off Alzheimer’s Signatures in the Hippocampus

Few would challenge the notion that a physically active life is better for the body, including the brain, than one spent parked on the couch. Exercise also reportedly sharpens the mind and fends off AD. However, the molecular mechanisms involved have been hard to pin down, and likely involve coordinated responses among different cell types. A new study published in Nature Neuroscience on June 12 zoomed in to the single-cell level to investigate how physical activity skews the gene-expression signatures in the dentate gyrus of the hippocampus, where the birth of newborn neurons continues into adulthood. The experiments pegged suites of genes that changed in response to wheel sessions, including amyloidosis signatures that were dampened or erased. What’s more, the scientists, led by Christiane Wrann of Massachusetts General Hospital in Boston, found that running revved up a disease-associated signature in microglia known to enhance clearance of amyloid plaques, and bolstered a newly identified breed of astrocyte associated with the vasculature. Perhaps surprisingly, oligodendrocyte precursor cells mounted the strongest response to wheel time.

  • In mice, exercise spurred neurogenesis in wild-type and APP/PS1 mice.
  • The workouts induced protective gene-expression signatures across cell types in the dentate gyrus.
  • Exercise reversed some of the gene-expression changes caused by amyloidosis.

The findings hint at ways in which regular exercise might thwart age-related neurodegenerative diseases, including AD.

The majority of observational studies on physical activity suggests that even light everyday movement protects the brain. It slows atrophy, rebuffs the encroachment of Aβ and tau pathologies, and staves off cognitive decline (May 2012 news; Apr 2019 news; Jul 2019 conference news; Jan 2019 news). According mostly to rodent studies, exercise also spurs neurogenesis, which takes place deep within the dentate gyrus of the hippocampus (May 2002 news; Sep 2019 news). This well of newborn neurons is thought to bolster memory and thwart the detrimental influence of amyloidosis (Tapia-Rojas et al., 2015). 

Besides the newborn neurons themselves, numerous other cell types, including adolescent and mature neurons, microglia, astrocytes, oligodendrocytes, and vascular cells, mingle within this neuronal nursery. To investigate all of them, first author Joana da Rocha and colleagues ran single-nucleus RNA sequencing on the dentate gyri of wild-type and APP/PS1 mice. First, the scientists established that in both types of mice, regular running spurred neurogenesis in the dentate gyrus. It also bolstered cognitive flexibility—a neurogenesis-dependent function tested by moving the location of a hidden platform in the Morris water maze test (Garthe and Kempermann, 2013). Notably, both neurogenesis and cognitive flexibility were deficient in APP/PS1 relative to wild-type mice, and exercise corrected these deficits.

Next, the scientists surveyed the transcriptomes of some 113,625 nuclei plucked from the dentate gyri of 20 mice. They identified 11 major brain-cell types, including neurons in different stages of development. Overall, exercise induced significant changes in gene expression across cell types, and many of these differed between wild-type and amyloidosis mice.

Focusing on developing neurons, the scientists identified genes that were dysregulated in APP/PS1 mice but shifted back toward normalcy by exercise. Many of these recovered genes are important for mitochondrial or lysosomal function, including ATP synthase inhibitory factor 1 (Atpif1), ATP/ADP translocase, solute carrier family 25 member 4 (Slc25a4), and ATPase H+-transporting V0 subunit (Atp6v0c). In cell culture assays, the scientists found that Atpif1 and Atp6v0c, in particular, were critical for neurogenesis, and protected cultured neurons from cytotoxicity induced by Aβ oligomers. The findings suggested that exercise promotes neuroprotective and neurogenic genes that had been downregulated by amyloidosis.

In microglia, exercise enhanced, rather than thwarted, an AD-associated signature. In APP/PS1 mice, the scientists found two transcriptomic clusters of microglia—one that was homeostatic; the other, disease-associated microglia (DAM). In wild-type mice, DAM were nearly absent. In response to exercise in APP/PS1 mice, both numbers of DAM, as well as their expression of DAM signature genes, increased. Because DAM are involved in beneficial responses such as clearance of Aβ plaques, the scientists interpreted their exercise-induced uptick as a good thing.

Exercise also spurred changes in astrocytes, normalizing expression of 48 of the 193 genes that were dysregulated in APP/PS1 mice. Across all mice, the scientists spotted two main transcriptional clusters of astrocyte. One was sparse in APP/PS1 mice relative to wild-type, and even more so among mice with no access to a running wheel. This particular cluster expressed high levels of cadherin-4, a calcium-dependent cell-cell adhesion protein that promotes angiogenesis. Looking at these CDH4-high astrocytes via immunofluorescence revealed that they formed abundant contacts with other astrocytes in the hippocampus, and they buddied up closely with the vasculature. The scientists dubbed these seemingly beneficial cells neurovascular astrocytes (NVAs).

Last but not least, in oligodendrocyte progenitor cells, 25 of the 39 genes that were skewed by amyloidosis were restored toward normal levels by exercise. Stearoyl-CoA desaturase 2 (Scd2), which encodes an enzyme necessary for production of the protective myelin sheath, was restored to almost wild-type levels in running APP/PS1 mice. This suggested that the workouts bolstered neuroprotective properties of these cells.

The study investigated changes in multiple other cell types as well, identifying exercise-induced changes across the board. The scientists also compared their mouse data to single-cell transcriptomics data from people with AD as well as controls, identifying substantial overlaps in the AD-induced signatures across species.

Overall, the scientists believe their snRNA-Seq dataset could be a starting point to discover mechanisms by which exercise protects the brain against AD and other age-related scourges.—Jessica Shugart

Comments

  1. In this exciting study, Joana da Rocha, Christiane Wrann, and colleagues, provide new information on how enhanced adult hippocampal neurogenesis (AHN) and exercise affect hippocampal function in Alzheimer’s disease. This study aligns with our previous work showing that enhancing AHN rescued learning and memory in FAD mice by restoring recruitment of immature neurons into the memory circuit and rescuing the transcription profile of the hippocampus (Mishra et al., 2022; Morrissey et al., 2025). 

    Particularly exciting is the new information on the neurovascular unit. Here, they identified a subpopulation of neurovascular-associated, CDH4high astrocytes that was scarce in AD and swelled with exercise. Cross information with human datasets showed that this population was increased in carriers of rs1582763-A, an intergenic allele associated with decreased risk for AD and high levels of sTREM2 in the cerebrovascular fluid. Little is known about the neurovascular unit in the hippocampus and of AHN specifically, and particularly in the context of AD. Additional studies should explore the neurovascular unit of AHN in health and AD.

    References:

    Mishra R, Phan T, Kumar P, Morrissey Z, Gupta M, Hollands C, Shetti A, Lopez KL, Maienschein-Cline M, Suh H, Hen R, Lazarov O. Augmenting neurogenesis rescues memory impairments in Alzheimer's disease by restoring the memory-storing neurons. J Exp Med. 2022 Sep 5;219(9) Epub 2022 Aug 19 PubMed.

    Morrissey ZD, Kumar P, Phan TX, Maienschein-Cline M, Leow A, Lazarov O. Neurogenesis drives hippocampal formation-wide spatial transcription alterations in health and Alzheimer's disease. Front Dement. 2025;4:1546433. Epub 2025 Apr 16 PubMed.

    View all comments by Orly Lazarov

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References

News Citations

  1. Research Brief: Total Activity, Not Just Exercise, Keeps Mind Sharp
  2. Light Is Alright: Mild Physical Activity Comes With Larger Brain
  3. Physical Activity May Shield the Brain from the Onslaught of Aβ
  4. Dementia: Frailty Hastens It, Physical Activity Wards It Off
  5. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis
  6. 'Runner Plasma' Jogs Neurogenesis, Quells Neuroinflammation in Mice

Paper Citations

  1. Tapia-Rojas C, Aranguiz F, Varela-Nallar L, Inestrosa NC. Voluntary Running Attenuates Memory Loss, Decreases Neuropathological Changes and Induces Neurogenesis in a Mouse Model of Alzheimer's Disease. Brain Pathol. 2015 Mar 11; PubMed.
  2. Garthe A, Kempermann G. An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis. Front Neurosci. 2013;7:63. Epub 2013 May 3 PubMed.

Further Reading

Primary Papers

  1. da Rocha JF, Lance ML, Luo R, Schlachter P, Moreira L, Iqbal MA, Kuhn P, Gardner RS, Valaris S, Islam MR, Gassner GM, Mazuera S, Healy K, Shastri S, Hibbert NB, Moran-Figueroa KV, Haley EB, Pfeiffer RD, Aygar S, Kastanenka KV, Brase L, Harari O, Benitez BA, Tucker NR, Wrann CD. Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing. Nat Neurosci. 2025 Jun 12; Epub 2025 Jun 12 PubMed.

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