Since the discovery that mutations in the gene for PS1 cause familial Alzheimer's disease, there has been keen interest in investigating the mechanism by which PS1 mutations cause disease. It has been shown that PS1 associates with members of the catenin family of signalling molecules, but what the association signifies is unclear. In today's issue of Nature, Bruce Yankner and colleagues at Harvard Medical School report that normal PS1 acts to stabilize β-catenin, and that mutant forms of PS1 reduce β-catenin stability. Transgenic mice bearing mutant PS1 genes have increased degradation of β-catenin in their brains. Interestingly, AD patients with the PS1 mutation also have markedly reduced β-catenin. The attendant reduction in β-catenin signalling appears to increase the vulnerability of neurons to apoptosis triggered by β-amyloid. These findings suggest that individuals with the PS1 mutations are predisposed to early-onset AD because the mutation destablizes β-catenin and makes neurons more susceptible to cell death.—June Kinoshita
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- Zhang Z, Hartmann H, Do VM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Sommer B, van de Wetering M, Clevers H, Saftig P, De Strooper B, He X, Yankner BA. Destabilization of beta-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature. 1998 Oct 15;395(6703):698-702. PubMed.