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

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.