Molecular Basis of Cell and Developmental Biology
Amyloid-β Binds to the Extracellular Cysteine-rich Domain of Frizzled and Inhibits Wnt/β-Catenin Signaling*

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The amyloid-β peptide (Aβ) plays a major role in neuronal dysfunction and neurotoxicity in Alzheimer disease. However, the signal transduction mechanisms involved in Aβ-induced neuronal dysfunction remain to be fully elucidated. A major current unknown is the identity of the protein receptor(s) involved in neuronal Aβ binding. Using phage display of peptide libraries, we have identified a number of peptides that bind Aβ and are homologous to neuronal receptors putatively involved in Aβ interactions. We report here on a cysteine-linked cyclic heptapeptide (denominated cSP5) that binds Aβ with high affinity and is homologous to the extracellular cysteine-rich domain of several members of the Frizzled (Fz) family of Wnt receptors. Based on this homology, we investigated the interaction between Aβ and Fz. The results show that Aβ binds to the Fz cysteine-rich domain at or in close proximity to the Wnt-binding site and inhibits the canonical Wnt signaling pathway. Interestingly, the cSP5 peptide completely blocks Aβ binding to Fz and prevents inhibition of Wnt signaling. These results indicate that the Aβ-binding site in Fz is homologous to cSP5 and that this is a relevant target for Aβ-instigated neurotoxicity. Furthermore, they suggest that blocking the interaction of Aβ with Fz might lead to novel therapeutic approaches to prevent neuronal dysfunction in Alzheimer disease.

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This work was supported by grants from the Howard Hughes Medical Institute, Conselho Nacional de Desenvolvimento Científico e Tecnológico and Pronex-FAPERJ (to S. T. F.), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (to M. H. M. and S. T. F.), the Third World Academy of Sciences (to M. H. M.), and Fundação de Amparo à Pesquisa do Estado de São Paulo (to M. A. J. and L. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.