Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment

Endoplasmic reticulum stress (ERS) and its downstream signaling play a central role in neuroinflammation in Alzheimer's disease (AD). Among them, IRE1α, as a key sensor of ER stress, is a pivotal molecule connecting stress to inflammation. Its aberrant activation drives neuroinflammation, which in turn exacerbates Aβ deposition, Tau pathology, and cognitive decline. Therefore, targeting the IRE1α signaling pathway has become a potential strategy for AD intervention. Recent studies suggest that exercise can alleviate ER stress and directly or indirectly inhibit the excessive activation of IRE1α, thereby reducing its downstream inflammatory signals. This review aims to systematically elucidate the pathogenic mechanism of the IRE1α inflammatory signaling pathway in AD. It also focuses on exploring the evidence of the neuroprotective effect of exercise through regulating this pathway, providing new theoretical basis and direction for exercise-based prevention and treatment of AD.