Aβ and tau clearance through aerobic exercise: unveiling the β2-adrenergic receptor’s role in regulating autophagy-lysosomal pathways

TL;DR

This study explores how aerobic exercise helps clear harmful proteins in Alzheimer's disease by activating a specific receptor that boosts cellular cleanup processes.

Contribution

The study identifies the β2-adrenergic receptor as a key mediator of aerobic exercise's effects on autophagy-lysosomal pathways in Alzheimer's disease.

Findings

Aerobic exercise activates β2-AR signaling to promote lysosomal acidification and Aβ clearance via VMA21 upregulation.

Aerobic exercise enhances autophagosome–lysosome fusion through the β2-AR–RXRα–CHMP4B axis, promoting tau degradation.

Pharmacological inhibition of β2-AR abolishes the beneficial effects of aerobic exercise on proteostatic pathways.

Abstract

The systematic dissection of molecular mechanisms through which aerobic exercise (AE) mitigates neurodegenerative pathologies remains a significant challenge. Alzheimer’s disease (AD) is characterized by impaired autophagy-lysosomal flux and the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. We recently identified the β2-adrenergic receptor (β2-AR) as a key mediator of exercise-induced bene = d sought to dissect its role in regulating distinct proteostatic pathways. We revealed that AE activates β2-AR signaling to promote lysosomal acidification via upregulation of VMA21, an essential assembly factor for the vacuolar ATPase (V-ATPase) proton pump, thereby facilitating Aβ clearance. Concurrently, AE enhanced autophagosome–lysosome fusion through the β2-AR – retinoid X receptor alpha (RXRα) – charged multivesicular body protein 4B (CHMP4B) axis, promoting tau degradation. Critically, pharmacological inhibition of β2-AR fully abolished these effects. Here, we propose an integrated mechanism through which β2-AR activation by AE could coordinate dual autophagy-lysosomal recovery processes and suggest that targeting this pathway offers a promising therapeutic strategy for AD and related proteostatic disorders.

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