Treadmill Exercise Mitigates Alzheimer’s Pathology by Modulating Glial Polarization and Reducing Oligodendrocyte Precursor Cell Perivascular Clustering

ABSTRACT Purpose This study aimed to investigate the pathological responses of glial cells at different distances from amyloid plaques and the characteristics of oligodendrocyte precursor cells (OPCs) in perivascular clustering. Additionally, it sought to explore the impact of exercise training on AD pathology, specifically focusing on the modulation of glial responses and the effects of OPC perivascular clustering. Methods Three-month-old C57BL/6 and APP/PS1 mice were divided into four groups: wild-type sedentary, wild-type exercise, sedentary AD, and exercise AD groups. The Barnes maze test was conducted to analyze spatial learning and memory. Enzyme-linked immunosorbent assay (ELISA) analysis, Immunofluorescence staining, Fluro-Jade C staining, TUNEL staining, Sholl analysis, and 3D rendering analysis were employed to detect Aβ 1-42, tau hyperphosphorylation, typical amyloid plaques, abnormal tau phosphorylation, neuronal damage, apoptosis, neurodegeneration, microglial and astrocytic activation and phenotypic polarization, and OPC perivascular clustering. Results Behavioral results revealed that long-term exercise training ameliorated cognitive deficits in APP/PS1 mice. Histopathological analysis showed a reduction in amyloid deposition and decreased tau hyperphosphorylation. Immunofluorescence and Fluro-Jade C staining indicated that exercise attenuated neuronal damage, degeneration, and apoptosis. Sholl and 3D rendering analysis demonstrated that exercise mitigated spatially dependent glial phenotypic changes surrounding amyloid plaques in the AD cortex and hippocampus. Further, immunofluorescence staining revealed that exercise alleviated plaque-associated glial changes in these regions. Exercise also alleviated the reduction of microglial SIRPα and reduced synaptic loss mediated by microglial and astrocyte phagocytosis. Lastly, exercise mitigated OPC senescence and cellular senescence-induced OPC perivascular clustering in AD mice. Conclusions Exercise can counteract AD pathological features by modulating glial responses and reducing OPC senescence and perivascular clustering near amyloid plaques, highlighting its potential as a therapeutic strategy for AD.