Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis

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Abstract
Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease1,2,3,4. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown5,6. Here we show that presenilin-1 forms a complex with β-catenin in vivo that increases β-catenin stability. Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize β-catenin, and lead to increased degradation of β-catenin in the brains of transgenic mice. Moreover, β-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of β-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-β protein. Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of β-catenin, predisposing individuals to early-onset Alzheimer's disease.