Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling.
The amyloid-beta peptide (Abeta) plays a major role in neuronal dysfunction and neurotoxicity in Alzheimer disease. However, the signal transduction mechanisms involved in Abeta-induced neuronal dysfunction remain to be fully elucidated. A major current unknown is the identity of the protein receptor(s) involved in neuronal Abeta binding. Using phage display of peptide libraries, we have identified a number of peptides that bind Abeta and are homologous to neuronal receptors putatively involved in Abeta interactions. We report here on a cysteine-linked cyclic heptapeptide (denominated cSP5) that binds Abeta 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 Abeta and Fz. The results show that Abeta 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 Abeta binding to Fz and prevents inhibition of Wnt signaling. These results indicate that the Abeta-binding site in Fz is homologous to cSP5 and that this is a relevant target for Abeta-instigated neurotoxicity. Furthermore, they suggest that blocking the interaction of Abeta with Fz might lead to novel therapeutic approaches to prevent neuronal dysfunction in Alzheimer disease.
Magdesian
Margaret H
MH
Instituto de Bioquímica Médica, Programa de Bioquímica e Biofísica Celular, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Carvalho
Milena M V F
MM
Mendes
Fabio A
FA
Saraiva
Leonardo M
LM
Juliano
Maria A
MA
Juliano
Luiz
L
Garcia-Abreu
José
J
Ferreira
Sérgio T
ST
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D051157:Frizzled Receptors / Q000378:metabolism*; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D051157:Frizzled Receptors; D009842:Oligopeptides; D051153:Wnt Proteins; D051176:beta Catenin