Inhibitory effect of a presenilin 1 mutation on the Wnt signalling pathway by enhancement of β-catenin phosphorylation

Abstract

Mutations in the presenilin 1 (PS1) gene are the most common genetic factor underlying the development of early onset familial Alzheimer's disease (FAD). Accumulating evidence has shown that FAD-linked mutations of PS1 enhance the generation of amyloid-β (1-42) protein. Recently, β-catenin has been shown to interact with PS1. β-catenin is essential for the Wnt signalling pathway. However, the biological significance of the interaction between β-catenin and PS1 in this signalling pathway remains to be clarified. In this study, we investigated the effect of FAD-linked PS1 (M146L) mutation in the Wnt signalling pathway using the conditioned medium containing Wnt-3A. The expression of mutated PS1 inhibited the Wnt-3A-induced accumulation of β-catenin. Chase analysis of β-catenin in Wnt-3A-stimulated cells following cycloheximide treatment revealed that PS1 mutation enhanced the generation of the higher molecular mass form of β-catenin, most likely, ubiquitinated β-catenin. In addition, the expression of mutated PS1 elevated the level of phosphorylated β-catenin, which is targeted to the ubiquitin/ proteasome pathway. Thus, it appears that PS1 (M146L) mutation down-regulates the Wnt-3A-induced accumulation of β-catenin due to an increase in the level of phosphorylated β-catenin.