Amyloid-beta binds to the extracellular cysteine-rich domain of frizzled and inhibits wnt/beta-catenin signaling

Amyloid-beta binds to the extracellular cysteine-rich domain of frizzled and inhibits wnt/beta-catenin signaling

Author Magdesian, Margaret H. Google Scholar
Carvalho, Milena M. V. F. Google Scholar
Mendes, Fabio A. Google Scholar
Saraiva, Leonardo M. Google Scholar
Juliano, Maria Aparecida Autor UNIFESP Google Scholar
Juliano, Luiz Autor UNIFESP Google Scholar
Garcia-Abreu, Jose Google Scholar
Ferreira, Sergio T. Google Scholar
Institution Universidade Federal do Rio de Janeiro (UFRJ)
Universidade Federal de São Paulo (UNIFESP)
Abstract The amyloid-beta peptide (A beta) plays a major role in neuronal dysfunction and neurotoxicity in Alzheimer disease. However, the signal transduction mechanisms involved in A beta-induced neuronal dysfunction remain to be fully elucidated. A major current unknown is the identity of the protein receptor(s) involved in neuronal A beta binding. Using phage display of peptide libraries, we have identified a number of peptides that bind A beta and are homologous to neuronal receptors putatively involved in A beta interactions. We report here on a cysteine-linked cyclic heptapeptide (denominated cSP5) that binds A beta 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 A beta and Fz. the results show that A beta 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 A beta binding to Fz and prevents inhibition of Wnt signaling. These results indicate that the A beta- binding site in Fz is homologous to cSP5 and that this is a relevant target for A beta-instigated neurotoxicity. Furthermore, they suggest that blocking the interaction of A beta with Fz might lead to novel therapeutic approaches to prevent neuronal dysfunction in Alzheimer disease.
Language English
Date 2008-04-04
Published in Journal of Biological Chemistry. Bethesda: Amer Soc Biochemistry Molecular Biology Inc, v. 283, n. 14, p. 9359-9368, 2008.
ISSN 0021-9258 (Sherpa/Romeo, impact factor)
Publisher Amer Soc Biochemistry Molecular Biology Inc
Extent 9359-9368
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000254465800066

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