NeuralCipher Research overview
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Abstract Physical exercise alleviates motor deficits and neuropathology in Parkinson’s disease (PD), yet the underlying mechanisms remain elusive. Using a mouse model induced by α-synuclein (αSyn) preformed fibrils, we found that glymphatic transport was markedly impaired in PD mice, accompanied by disrupted perivascular aquaporin-4 (AQP4) polarization and αSyn accumulation. Chronic treadmill exercise restored glymphatic function, restored AQP4 polarity, and alleviated motor deficits and neuropathology; these effects were abrogated by AQP4 inhibition. We identified the exercise-induced myokine irisin as a critical systemic mediator linking peripheral activity to central clearance. Systemic irisin administration recapitulated the glymphatic benefits of exercise, whereas Fndc5 deficiency abolished them. Mechanistically, irisin acted on astrocytes to suppress STAT3 activation and upregulate the circadian gene Nr1d1 (encoding REV-ERBα). Astrocyte-specific knockdown of Nr1d1 disrupted AQP4 polarization and eliminated the glymphatic and neuroprotective effects of both exercise and irisin. Collectively, these findings establish an exercise-irisin-astrocyte axis that enhances glymphatic clearance of αSyn aggregates through REV-ERBα-dependent regulation of astrocytic function, revealing a previously unrecognized mechanism linking peripheral exercise to brain proteostasis.
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