Alzheimer's disease (AD) is a progressive neurodegenerative disorder, neuropathologically characterized by the presence of amyloid plaques, containning the amyloid-b peptide (Ab), in the limbic and cerebral cortices of affected individuals. Current evidence supports the notion that Ab plays a major role in neuronal dysfunction and neurotoxicity in AD. However, the signal transduction mechanisms involved remain to be elucidated. With the goal of identifying ligands that mediate the neuronal impact of Ab, we have used phage display of peptide libraries to identify peptide sequences that bind to Ab. Using this approach, we have isolated a cysteine-linked 7 amino acid peptide, here denominated SP, that binds to Ab. Homology comparison with the human protein sequence databank revealed that SP is highly homologous to the extracellular domain of several members of the Frizzled (Fz) family of Wnt receptors. Wnt proteins regulate a variety of biological processes, including development, cell movements, polarity, axon guidance and synapse formation. The interaction of Wnt proteins with Fz on the cell surface is the first step in the transduction of the extracellular signal into intracellular responses. Upon stimulation of the Wnt pathway, b-catenin degradation is inhibited and its accumulation and association with a family of transcription factors leads to the activation of Wnt-responsive genes. Here we show that Ab binds to the extracellular cysteine-rich domain of Fz at or in close proximity to the Wnt binding site. Moreover, Ab inhibit b-catenin accumulation, nuclear translocation and Wnt-targeted gene transcription. Interestingly, the SP peptide completely blocks Ab binding to Fz. These results indicate that the Ab binding site in Fz is homologous to SP and that this is a relevant target for Ab neurotoxicity. Furthermore, they suggest that blocking the interaction of Ab with Fz might lead to novel therapeutic approaches to prevent neuronal dysfunction in AD.
Supported by: CNPq, FAPERJ, Howard Hughes Medical Institute.