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

Zhuohua Zhang, Henrike Hartmann, Viet Minh Do, Dorothee Abramowski, Christine Sturchler-Pierrat, Matthias Staufenbiel, Bernd Sommer, Marc van de Wetering, Hans Clevers, Paul Saftig, Bart De Strooper, Xi He and Bruce A. Yankner ()
Additional contact information
Zhuohua Zhang: The Children's Hospital
Henrike Hartmann: The Children's Hospital
Viet Minh Do: The Children's Hospital
Dorothee Abramowski: Preclinical Research, Novartis Pharma Ltd
Christine Sturchler-Pierrat: Preclinical Research, Novartis Pharma Ltd
Matthias Staufenbiel: Preclinical Research, Novartis Pharma Ltd
Bernd Sommer: Preclinical Research, Novartis Pharma Ltd
Marc van de Wetering: University Hospital
Hans Clevers: University Hospital
Paul Saftig: Zentrum Biochemie und Molekular Zellbiologie, Universität Gottingen
Bart De Strooper: Flemish Institute for Biotechnology (VIB4), Center for Human Genetics
Xi He: The Children's Hospital
Bruce A. Yankner: The Children's Hospital

Nature, 1998, vol. 395, issue 6703, 698-702

Abstract: 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.

Date: 1998
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DOI: 10.1038/27208

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