Presenilin 1 facilitates the constitutive turnover of beta-catenin: Differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway

Although an association between the product of the familial Alzheimer's dis ease (FAD) gene, presenilin 1 (PS1), and beta-catenin has been reported rec ently, the cellular consequences of this interaction are unknown. Here, we show that both the full length and the C-terminal fragment of wild-type or FAD mutant PS1 interact with beta-catenin from transfected cells and brains of transgenic mice, whereas E-cadherin and adenomatous polyposis coli (APC ) are not detected in this complex. Inducible overexpression of PS1 led to increased association of beta-catenin with glycogen synthase kinase-3 beta (GSK-3 beta), a negative regulator of beta-catenin, and accelerated the tur nover of endogenous beta-catenin. In support of this finding, the beta-cate nin half-life was dramatically longer in fibroblasts deficient in PS1, and this phenotype was completely rescued by replacement of PS1, demonstrating that PS1 normally stimulates the degradation of beta-catenin. In contrast, overexpression of FAD-linked PS1 mutants (M146L and Delta X9) failed to enh ance the association between GSK-3 beta and beta-catenin and interfered wit h the constitutive turnover of beta-catenin. In vivo confirmation was demon strated in the brains of transgenic mice in which the expression of the M14 6L mutant PS1 was correlated with increased steady-state levels of endogeno us beta-catenin. Thus, our results indicate that PS1 normally promotes the turnover of beta-catenin, whereas PS1 mutants partially interfere with this process, possibly by failing to recruit GSK-3 beta into the PS1-beta-caten in complex. These findings raise the intriguing possibility that PS1-beta-c atenin interactions and subsequent activities may be consequential for the pathogenesis of AD.