The APP intracellular domain (AICD) inhibits Wnt signalling and promotes neurite outgrowth

β- and γ-secretase cleave the amyloid precursor protein (APP) to release the amyloidogenic β-amyloid peptides (Aβ) and the APP intracellular domain (AICD). Aβ has been widely believed to initiate pathogenic cascades culminating in Alzheimer's disease (AD). However, the physiological functions of the AICD remain elusive. In this study, we found the AICD to strongly inhibit Wnt-induced transcriptional reporter activity, and to counteract Wnt-induced c-Myc expression. Loss of the AICD resulted in an increased responsiveness to Wnt/β-catenin-mediated transcription. Mechanically, the AICD was found to interact with glycogen synthase kinase 3 beta (GSK3β) and promote its kinase activity. The subsequent AICD-strengthened Axin–GSK3β complex potentiates β-catenin poly-ubiquitination. Functional studies in N2a mouse neuroblastoma cells, rat pheochromocytoma PC12 cells and primary neurons showed that the AICD facilitated neurite outgrowth. And AICD antagonised Wnt3a-suppressed growth arrest and neurite outgrowth in N2a and PC12 cells. Taken together, our results identify the AICD as a novel inhibitory factor of the canonical Wnt signalling pathway and suggest its regulatory role in neuronal cell proliferation and differentiation.

► AICD inhibits canonical Wnt signalling and reduces Wnt induced c-Myc expression.
► AICD antagonises Wnt signalling in GSK3β kinase activity dependent manner.
► AICD associates with and activates GSK3β.
► AICD cooperates with NGF to suppress neuronal cell proliferation.
► AICD antagonises Wnt suppressed and promotes NGF induced neurite outgrowth.