SEC62-mediated ER-phagy activation alleviates Alzheimer's disease pathology and restores cognitive function in 5×FAD mice.

Alzheimer's disease (AD) is a common age-related neurodegenerative disorder. Previous studies have shown that patients with AD exhibit dysregulation of endoplasmic reticulum (ER) homeostasis in the brain, such as ER stress and ER damage. As a type of selective autophagy that specifically clears damaged ER, ER-phagy plays a key role in ER quality control, but the role in AD progression remains elusive. In this study, we found that ER homeostasis is severely disrupted in the pathological state of AD, characterized by enhanced ER stress response, the presence of ER damage, and concurrent defects in ER-phagy function. Notably, some receptors mediating ER-phagy were decreased in neurons differentiated from induced pluripotent stem cells (iPSCs) derived from AD patients and in 5×FAD mouse samples. Interestingly, overexpression of the ER-phagy receptor SEC62 in the brain of 5×FAD mice via intrathecal AAV injection markedly alleviated disease phenotypes, including β-amyloid (Aβ) plaque deposition, neuroinflammation, and cognitive impairment. These results indicate that restoring ER-phagy activity provides a potential strategy for the treatment of AD.