Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats.
Overview
- Department of Environmental and Radiologic Health Sciences, Colorado State University, Fort Collins, CO, United States
- Department of Anatomy and Physiology, Kansas State University, Manhattan, KS, United States
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder world-wide, characterized by progressive neuroinflammation, aberrant protein accumulation, and neuronal loss associated with cognitive decline. Although our understanding of the molecular mechanisms underlying AD pathogenesis has greatly increased in recent years, there remain limited treatment strategies and no cures for this disorder. Because of this, efforts have shifted toward identifying modifiable lifestyle factors which may decrease risk of onset or slow AD progression. One such approach which has shown promise in modulating the disease course is physical exercise. However, sex-specific effects of implementing such activity strategies in aged individuals after the onset of disease are less well studied. We sought to address this knowledge gap by characterizing hippocampal histopathology and DNA modification profiles of aged TgF344-AD rats following progressive treadmill-training. Reduced-representation bisulfite sequencing indicated 94 genes associated with differentially modified cytosines (DMCs) in exercised females (239 differentially modified regions, 54.6% hypermodified) and 87 DMC-associated genes in exercised males (216 differentially modified regions, 50.4% hypermodified) with unique functional enrichment for overrepresented pathways and protein interactions relevant to glial activation and synaptic plasticity. Using quantitative high-throughput slide scanning fluorescence microscopy we additionally examined this brain region for AD-relevant changes including neuronal and microglial density, microglial morphology, and accumulation of pathologic protein. This analysis revealed female-specific reductions in NeuN+ and Iba1+ cells in treadmill-trained animals, as well as sex- and exercise-dependent changes in plaque-associated microglial reactivity state. Together, these findings reveal that age of onset, biologic sex, and duration of physical exertion may be important factors in modulating the pathologic progression of AD.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- doi:10.5061/
dryad.w0vt4b978 , at Dryad; found in “Data availability statement”
Data availability statement
The RRBS datasets analyzed in this study are publicly available in the Dryad Digital Repository at DOI: Dryad Digital Repository 10.5061/
Reproduced under the paper's license (CC BY), from the paper cited above.
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 9 authors, 5 keywords, 75 references.
Cite
This paper
Schuller, A. J., Hager, M. R., Briggs, A. M., Rocha, S. M., Yanouri, O. A., Smith, E. J., Hall, S. E., Montrose, L. B., & Tjalkens, R. B. (2026). Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats. Frontiers in neuroscience, 20, 1805957. https://
BibTeX
@article{schuller2026tre
author = {Schuller, Adam J and Hager, Megan R and Briggs, Aidan M and Rocha, Savannah M and Yanouri, Omar A and Smith, Emma J and Hall, Stephanie E and Montrose, Luke B and Tjalkens, Ronald B},
title = {{Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats}},
journal = {Frontiers in neuroscience},
year = {2026},
month = may,
volume = {20},
pages = {1805957},
publisher = {Frontiers Media SA},
issn = {1662-4548},
doi = {10.3389/
url = {https://
pmid = {42164431},
pmcid = {PMC13185687}
}
RIS
TY - JOUR
AU - Schuller, Adam J
AU - Hager, Megan R
AU - Briggs, Aidan M
AU - Rocha, Savannah M
AU - Yanouri, Omar A
AU - Smith, Emma J
AU - Hall, Stephanie E
AU - Montrose, Luke B
AU - Tjalkens, Ronald B
TI - Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats
T2 - Frontiers in neuroscience
J2 - Front Neurosci
PY - 2026
DA - 2026/
VL - 20
SP - 1805957
SN - 1662-4548
PB - Frontiers Media SA
DO - 10.3389/
UR - https://
LA - en
ER -
CSL-JSON
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