Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial...

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.