Overexpression of AICD and Arc Drives APP Processing and Aggregate Formation in Drosophila

Abnormal amyloid precursor protein (APP) processing, specifically cleavage through the amyloidogenic pathway creates amyloid-beta proteins that when oligomerized, causes brain damage and is a hallmark of Alzheimer's disease. Here, we examine how AICD and Arc expression affect APP localization and processing in Drosophila. Immunohistochemistry revealed that AICD overexpression induces Arc expression and leads to APP clustering and accumulation, which are not present in controls. Western blot analysis showed that Arc-GFP expression generates additional APP-related species, possibly by-products of APP proteolysis. This includes AICD, which drives the feed-forward loop in APP cleavage and Alzheimer’s Disease. Furthermore, long-term memory (LTM) training increased APP cleavage in MBON-5β neurons, which in turn causes increased AICD and sAPP levels. These findings suggest that Arc and AICD are the main components in APP proteolysis, and memory related activity further drives the feed-forward loop in vivo.