Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis.
Zhang, Zhuohua; Hartmann, Henrike; , Viet Minh Do; Abramowski, Dorothee; Sturchler-Pierrat, Christine; Staufenbiel, Matthias; Sommer, Bernd; van de Wetering, Marc; Clevers, Hans; Saftig, Paul; De Strooper, Bart; He, Xi; Yankner, Bruce A.
[Letter] Nature. 395(6703):698-702, October 15, 1998.

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Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease [1-4]. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown [5,6]. 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.

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