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The Journal of Neuroscience, June 1, 1999, 19(11):4229-4237

Presenilin 1 Facilitates the Constitutive Turnover of -Catenin: Differential Activity of Alzheimer's Disease-Linked PS1 Mutants in the -Catenin-Signaling Pathway

David E. Kang¹, Salvador Soriano¹, Matthew P. Frosch^{2, 3}, Tucker Collins³, Satoshi Naruse⁴, Sangram S. Sisodia⁴, Gil Leibowitz⁵, Fred Levine⁵, and Edward H. Koo¹

Departments of ¹ Neurosciences and ⁵ Pediatrics, University of California, San Diego, La Jolla, California 92093, ² Center for Neurological Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, ³ Department of Pathology, Harvard Medical School, and Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, and ⁴ Department of Pharmacological and Physiological Science, University of Chicago, Chicago, Illinois 60637

Although an association between the product of the familial Alzheimer's disease (FAD) gene, presenilin 1 (PS1), and -catenin has been reported recently, the cellular consequences of this interaction are unknown. Here, we show that both the full length and the C-terminal fragment of wild-type or FAD mutant PS1 interact with -catenin from transfected cells and brains of transgenic mice, whereas E-cadherin and adenomatous polyposis coli (APC) are not detected in this complex. Inducible overexpression of PS1 led to increased association of -catenin with glycogen synthase kinase-3 (GSK-3), a negative regulator of -catenin, and accelerated the turnover of endogenous -catenin. In support of this finding, the -catenin half-life was dramatically longer in fibroblasts deficient in PS1, and this phenotype was completely rescued by replacement of PS1, demonstrating that PS1 normally stimulates the degradation of -catenin. In contrast, overexpression of FAD-linked PS1 mutants (M146L and X9) failed to enhance the association between GSK-3 and -catenin and interfered with the constitutive turnover of -catenin. In vivo confirmation was demonstrated in the brains of transgenic mice in which the expression of the M146L mutant PS1 was correlated with increased steady-state levels of endogenous -catenin. Thus, our results indicate that PS1 normally promotes the turnover of -catenin, whereas PS1 mutants partially interfere with this process, possibly by failing to recruit GSK-3 into the PS1--catenin complex. These findings raise the intriguing possibility that PS1--catenin interactions and subsequent activities may be consequential for the pathogenesis of AD.

Key words: presenilin; -catenin; glycogen synthase kinase-3; immunoprecipitation; turnover; half-life; Alzheimer's disease

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19114229-09$05.00/0

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