Multiple ligand binding sites on Aβ(1–40) fibrils

Abstract

Although the structures of Thioflavin T and another benzothiazole, BTA-1, are similar, they bind to Aß non-competitively, probably to different sites on the Aß (1–40) fibrils. The amyloid fibril-induced fluorescence of ThT that corresponds to a fraction of total ThT binding is not displaced by high concentrations of (S)-naproxen or (R)-ibuprofen, which are reported to potently block high affinity binding of the radiolabeled malononitrile FDDNP and derivatives. The binding of the benzothiazole ligands is significantly substoichiometric with respect to Aß (1–40) monomer peptide, unlike Congo Red, which binds to Aß (1–40) fibrils on a 1:1 basis with monomer peptide. These results indicate that there are multiple domains for ligand binding to amyloid fibrils and suggest that it may be possible to design ligands that bind selectively to particular forms of fibrils that are connected with the pathogenesis of Alzheimer's disease and potentially other protein misfolding diseases.