Wnt/β-catenin signal pathway stabilizes APP intracellular domain (AICD) and promotes its transcriptional activity

Amyloid precursor protein (APP), a key protein in pathogenesis of Alzheimer’s disease (AD), is a type I transmembrane protein which can be cleaved by β- and γ-secretase to release the amyloidogenic β-amyloid peptides (Aβ) and the APP intracellular domain (AICD). While Aβ has been widely believed to initiate pathogenic cascades culminating AD, the physiological functions and regulations of AICD remain elusive. In present study, endogenous AICD was demonstrated to be increased by canonical Wnt signal. Instead of due to γ-secretase activity, enhanced AICD expression was found due to the increased protein stability by Wnt/β-catenin. β-Catenin was demonstrated to be an associating partner of AICD, capable of promoting AICD mediated transcriptional activity. Investigation by AICD mutants proved that Fe65, a previously identified AICD binding partner, is not involved in this regulation. Taken together, our results suggest that AICD is stabilized and the AICD mediated transcriptional activity is promoted by canonical Wnt/β-catenin signaling independent of Fe65.

► Wnt activation increases endogenous AICD expression independent of γ-secretase activity.
► Wnt/β-catenin signaling pathway stabilizes AICD.
► β-Catenin interacts with AICD and promotes its transcriptional activity.
► Wnt/β-catenin stabilizes AICD in Fe65 independent manner.