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Nature. 1998 Oct 15;395(6703):698-702.

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

Author information

1
Department of Neurology, Harvard Medical School, The Children's Hospital, Boston, Massachusetts 02115, USA.

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.

PMID:
9790190
DOI:
10.1038/27208
[Indexed for MEDLINE]

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