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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenomatous Polyposis Coli Protein
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Alzheimer Disease / etiology*
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism
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Animals
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Apoptosis*
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Brain / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Line
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Cytoskeletal Proteins / metabolism*
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Endoplasmic Reticulum / metabolism
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Glycogen Synthase Kinase 3
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Golgi Apparatus / metabolism
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Transgenic
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Microscopy, Fluorescence
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Mutation
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Neurons / pathology*
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Presenilin-1
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Rats
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Signal Transduction
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Trans-Activators*
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beta Catenin
Substances
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Adenomatous Polyposis Coli Protein
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Amyloid beta-Peptides
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Ctnnb1 protein, rat
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Cytoskeletal Proteins
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Membrane Proteins
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PSEN1 protein, human
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Presenilin-1
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Trans-Activators
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beta Catenin
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3