LAUSR

The amyloid precursor protein (APP) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). While the production of Amyloid beta (Aβ) has traditionally been considered the primary cause of AD, the role of the APP intracellular domain (AICD) remains largely elusive. In this study, we established a novel model in the adult fly wing by expressing human APP, recapitulating AD‐associated axon degeneration. Using this model, we discovered that ectopic APP expression in Drosophila wing margin neurons led to age‐dependent axon degeneration. APP's effect depended on AICD production, and AICD overexpression alone was sufficient to induce axon degeneration in adult wings. Further investigations indicated that APP‐ or AICD‐induced axon degeneration could be alleviated by blocking autophagy, but not apoptosis. Additionally, we identified a FoxO/Snail–Atg1 axis as an essential mediator of APP/AICD‐induced autophagy‐dependent axon degeneration. Finally, we demonstrated that administration of chloroquine, an autophagy inhibitor, effectively ameliorates APP‐ or AICD‐induced axon degeneration. Our findings provide crucial insights into how APP induces autophagy‐dependent axon degeneration through AICD production, laying a foundation for future investigations into AD pathogenesis.