title: Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis.
abstract: Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown. Here we show that presenilin-1 forms a complex with beta-catenin in vivo that increases beta-catenin stability. Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize beta-catenin, and lead to increased degradation of beta-catenin in the brains of transgenic mice. Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of beta-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-beta protein. Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of beta-catenin, predisposing individuals to early-onset Alzheimer's disease.
authors.affiliation: Department of Neurology, Harvard Medical School, The Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Hartmann
authors.forename: V M
authors.initials: VM
authors.lastname: Do
authors.forename: D
authors.initials: D
authors.lastname: Abramowski
authors.forename: C
authors.initials: C
authors.lastname: Sturchler-Pierrat
authors.forename: M
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: B
authors.initials: B
authors.lastname: Sommer
authors.forename: M
authors.initials: M
authors.lastname: van de Wetering
authors.forename: H
authors.initials: H
authors.lastname: Clevers
authors.forename: P
authors.initials: P
authors.lastname: Saftig
authors.forename: B
authors.initials: B
authors.lastname: De Strooper
authors.forename: X
authors.initials: X
authors.lastname: He
authors.forename: B A
authors.initials: BA
authors.lastname: Yankner
mesh_terms: D025601:Adenomatous Polyposis Coli Protein; D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D009474:Neurons / Q000473:pathology*; D053764:Presenilin-1; D051381:Rats; D015398:Signal Transduction; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D016229:Amyloid beta-Peptides; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D015534:Trans-Activators; D051176:beta Catenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3