Substitution of a Glycogen Synthase Kinase-3β Phosphorylation Site in Presenilin 1 Separates Presenilin Function from β-Catenin Signaling

Abstract

The majority of cases with early onset familial Alzheimer's disease have been attributed to mutations in the presenilin 1 (PS1) gene. PS1 protein is a component of a high molecular weight membrane-bound complex that also contains β-catenin. The physiological relevance of the association between PS1 and β-catenin remains controversial. In this study, we report the identification and functional characterization of a highly conserved glycogen synthase kinase-3β consensus phosphorylation site within the hydrophilic loop domain of PS1. Site-directed mutagenesis, together with in vitro and in vivo phosphorylation assays, indicates that PS1 residues Ser353 and Ser357 are glycogen synthase kinase-3β targets. Substitution of one or both of these residues greatly reduces the ability of PS1 to associate with β-catenin. By disrupting this interaction, we demonstrate that the association between PS1 and β-catenin has no effect on Aβ peptide production, β-catenin stability, or cellular susceptibility to apoptosis. Significantly, in the absence of PS1/β-catenin association, we found no alteration in β-catenin signaling using induction of this pathway by exogenous expression of Wnt-1 or β-catenin and a Tcf/ Lef transcriptional assay. These results argue against a pathologically relevant role for the association between PS1 and β-catenin in familial Alzheimer's disease.