title: Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway.
abstract: Although an association between the product of the familial Alzheimer's disease (FAD) gene, presenilin 1 (PS1), and beta-catenin has been reported recently, 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-3beta (GSK-3beta), a negative regulator of beta-catenin, and accelerated the turnover of endogenous beta-catenin. In support of this finding, the beta-catenin 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 DeltaX9) failed to enhance the association between GSK-3beta and beta-catenin and interfered with the constitutive turnover of beta-catenin. In vivo confirmation was demonstrated in the brains of transgenic mice in which the expression of the M146L mutant PS1 was correlated with increased steady-state levels of endogenous 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-3beta into the PS1-beta-catenin complex. These findings raise the intriguing possibility that PS1-beta-catenin interactions and subsequent activities may be consequential for the pathogenesis of AD.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Kang
authors.forename: S
authors.initials: S
authors.lastname: Soriano
authors.forename: M P
authors.initials: MP
authors.lastname: Frosch
authors.forename: T
authors.initials: T
authors.lastname: Collins
authors.forename: S
authors.initials: S
authors.lastname: Naruse
authors.forename: S S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: G
authors.initials: G
authors.lastname: Leibowitz
authors.forename: F
authors.initials: F
authors.lastname: Levine
authors.forename: E H
authors.initials: EH
authors.lastname: Koo
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D015820:Cadherins / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D053764:Presenilin-1; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D053764:Presenilin-1; D015534:Trans-Activators; D051176:beta Catenin; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3