Reticulophagy limits Alzheimer’s disease pathology through FAM134B-dependent APP clearance

Selective autophagy maintains organelle and proteome homeostasis through receptor-mediated degradation of damaged membranes and aggregation-prone proteins. Although autophagy dysfunction and endoplasmic reticulum (ER) abnormalities are prominent features of Alzheimer's disease (AD), whether reticulophagy directly contributes to amyloid precursor protein (APP) turnover has remained unclear. We identify FAM134B/RETREG1 as a specific receptor that recognizes ER-localized APP and promotes its lysosomal degradation through LC3-dependent reticulophagy. In AD patient samples and 5XFAD mice, epigenetic repression of FAM134B limits TFEB/TFE3-dependent transcription, resulting in impaired ER turnover, APP accumulation, and exacerbated amyloid pathology. Restoration of wild-type, but not LIR-mutant, FAM134B rescues reticulophagy, reduces APP and Aβ accumulation, preserves neuronal integrity, and improves cognition in 5XFAD mice. These findings establish impaired reticulophagy as an upstream pathogenic mechanism in AD and highlight FAM134B-mediated ER turnover as a potential therapeutic strategy for limiting amyloidogenic APP accumulation.