Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis
Zhang, Z × Hartmann, H Do, V M Abramowski, D Sturchler-Pierrat, C Staufenbiel, M Sommer, B van de Wetering, M Clevers, H Saftig, P De Strooper, Bart He, X Yankner, B A #
Nature vol:395 issue:6703 pages:698-702
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.