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

The majority of cases with early onset familial Alzheimer's disease have be en attributed to mutations in the presenilin 1 (PSI) gene. PS1 protein is a component of a high molecular weight membrane-bound complex that also cont ains beta -catenin, The physiological relevance of the association between PS1 and beta -catenin remains controversial. In this study, we report the i dentification and functional characterization of a highly conserved glycoge n synthase binase-3 beta consensus phosphorylation site within the hydrophi lic loop domain of PS1, Site-directed mutagenesis, together with in vitro a nd in vivo phosphorylation assays, indicates that PS1 residues Ser(353) and Ser(357)are glycogen synthase kinase-3 beta targets. Substitution:of one o r both of these residues greatly reduces the ability of PS1 to associate wi th beta -catenin. By disrupting this interaction, we demonstrate that the a ssociation between PSI and beta -catenin has no effect on A beta peptide pr oduction, beta -catenin stability, or cellular susceptibility to apoptosis. Significantly, in the absence of PS1/beta -catenin association, we found n o alteration in beta -catenin signaling using induction of this pathway by exogenous expression of Wnt-1 or beta -catenin and a Tcf/Lef transcriptiona l assay. These results argue against a pathologically relevant role for the association between PS1 and beta -catenin in familial Alzheimer's disease.