Depending on intensity, exercise improved or worsened pathology in a model of prodromal Parkinson's disease.

Exercise is increasingly applied as non-pharmacological intervention in Parkinson's disease (PD). While evidence suggests beneficial effects, the mechanisms, optimal intensity, and potential risks remain unclear. This study investigated the effects of treadmill exercise on motor and non-motor symptoms, alpha-synuclein pathology, neuroinflammation, and gut microbiota composition in Thy1-aSyn transgenic mice, a model of prodromal PD. Moderate (5 m/min) or intensive (12.5-15 m/min) treadmill exercise three times a week for one month delayed motor deficits, with improvements in beam-walking performance and gait coordination. Intensive training attenuated anxiety-like behavior and reduced phosphorylated alpha-synuclein accumulation in the substantia nigra, but not in limbic regions, demonstrating region-specific pathology modulation. Despite absent baseline neuroinflammation, intensive exercise increased microglial reactivity in the amygdala and hippocampus. Additionally, exercise increased fecal microbiota diversity across genotypes, with selective enrichment of Lachnospiraceae. These findings suggest that exercise modulates PD-related pathology and motor symptoms, although intensity-dependent limbic microgliosis warrants further investigation.