Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis (original) (raw)

Nature volume 395, pages 698–702 (1998)Cite this article

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.

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Acknowledgements

We thank D. Nochlin, C. Lippa, T. Bird, C. Rosenberg, A. Roses, D. Pollin and J. Rogers for autopsy human brain tissue; K. Burki and B. Lederman for assistance in the generation of transgenic mice; and Y. Sun for discussions. This work was supported by grants from the NIH, the Alzheimer's Association and Novartis Pharma Ltd (to B.A.Y.), an NIH training grant and a fellowship from The Medical Foundation (to Z.Z.), a fellowship from the Deutsche Forschungsgemeinschaft (to H.H.), a Pew Scholarship (to X.H.), and an NIH MRRC Core Grant.

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Authors and Affiliations

  1. Department of Neurology, Harvard Medical School and Division of Neuroscience, The Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA
    Zhuohua Zhang, Henrike Hartmann, Viet Minh Do, Xi He & Bruce A. Yankner
  2. Preclinical Research, Novartis Pharma Ltd, CH-4002, Basel, Switzerland
    Dorothee Abramowski, Christine Sturchler-Pierrat, Matthias Staufenbiel & Bernd Sommer
  3. Department of Immunology, University Hospital, 3508, GA Utrecht, The Netherlands
    Marc van de Wetering & Hans Clevers
  4. Abteilung Biochemie II, Zentrum Biochemie und Molekular Zellbiologie, Universität Gottingen, 37073, Gottingen, Germany
    Paul Saftig
  5. Flemish Institute for Biotechnology (VIB4), Center for Human Genetics, B-3000, K.U. Leuven, Belgium
    Bart De Strooper

Authors

  1. Zhuohua Zhang
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  2. Henrike Hartmann
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  3. Viet Minh Do
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  4. Dorothee Abramowski
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  5. Christine Sturchler-Pierrat
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  6. Matthias Staufenbiel
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  7. Bernd Sommer
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  8. Marc van de Wetering
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  9. Hans Clevers
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  10. Paul Saftig
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  11. Bart De Strooper
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  12. Xi He
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  13. Bruce A. Yankner
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Correspondence toBruce A. Yankner.

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Zhang, Z., Hartmann, H., Minh Do, V. et al. Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis.Nature 395, 698–702 (1998). https://doi.org/10.1038/27208

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