Aerobic Exercise Attenuates Autophagy‐Lysosomal Flux Deficits via β2‐AR‐Mediated ESCRT‐III Subunit CHMP4B in Mice With Human MAPT P301L

ABSTRACT Deficits in the autophagy‐lysosomal pathway facilitate intracellular microtubule associated protein tau (MAPT) accumulation in Alzheimer disease (AD). Aerobic exercise (AE) has been recommended as a way to delay and treat AD, but the exact effects and mechanisms have not been fully elucidated. Here, we found that AE (8‐week treadmill running, 40 min/day, 5 days/week) alleviated autophagy‐lysosomal defects and MAPT pathology through the activation of β2‐adrenergic receptors (β2‐AR) in MAPT P301L mice. Molecular mechanistic investigations revealed that endosomal sorting complex required for transport (ESCRT) III subunit charged multivesicular body protein 4B (CHMP4B), which is essential for autophagosome‐lysosome fusion, was significantly decreased in the cerebral cortex of AD patients and the hippocampus of MAPT P301L mice. AE restored the levels of CHMP4B, which reversed autophagy‐lysosomal defects and reduced MAPT aggregation. Inhibition of β2‐AR by propranolol (30 mg/kg, intragastric administration 1 h before each AE session) restrained AE‐attenuated MAPT accumulation by inhibiting autophagy‐lysosomal flux in MAPT P301L mice. Our findings suggest that AE can alleviate autophagosome‐lysosome fusion deficits by promoting the β2‐AR‐RXRα‐CHMP4B‐ESCRT–III pathway, reducing pathological MAPT aggregation, which also reveals a novel theoretical basis for AE attenuating AD progression.