Substitution of a glycogen synthase kinase-3β phosphorylation site in presenilin 1 separates presenilin function from β-catenin signaling

The majority of cases with early onset familial Alzheimer's disease have been attributed to mutations in the presenilin 1 (PSI) gene. PS1 protein is a component of a high molecular weight membrane-bound complex that also contains beta -catenin, The physiological relevance of the association between PS1 and beta -catenin remains controversial. In this study, we report the identification and functional characterization of a highly conserved glycogen synthase binase-3 beta 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 Ser(353) and Ser(357)are glycogen synthase kinase-3 beta targets. Substitution:of one or both of these residues greatly reduces the ability of PS1 to associate with beta -catenin. By disrupting this interaction, we demonstrate that the association between PSI and beta -catenin has no effect on A beta peptide production, beta -catenin stability, or cellular susceptibility to apoptosis. Significantly, in the absence of PS1/beta -catenin association, we found no alteration in beta -catenin signaling using induction of this pathway by exogenous expression of Wnt-1 or beta -catenin and a Tcf/Lef transcriptional assay. These results argue against a pathologically relevant role for the association between PS1 and beta -catenin in familial Alzheimer's disease.