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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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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DOI: https://doi.org/10.1038/27208
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