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

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.