Structurally distinct toxicity inhibitors bind at common loci on β-amyloid fibril

The accumulation of aggregated beta-Amyloid (A beta) in the brain is a hallmark of Alzheimer's disease and is thought to play a role in the neurotoxicity associated with the disease The mechanism by which A beta aggregates induce toxicity is uncertain Nonetheless, several small molecules have been found to interact with A beta fibrils and to prevent their toxicity In this paper we studied the binding of these known toxicity inhibitors to A beta fibrils, as a means to explore surfaces or loci on A beta aggregates that may be significant in the mechanism of action of these inhibitors We believe knowledge of these binding loci will provide insight into surfaces on the A beta fibrils important in A beta biological activity The program DOCK was used to computationally dock the inhibitors to an A beta fibril The inhibitors docked at two shared binding loci, near Lys28 and at the C-termini near Asn27 and Val39 The docking predictions were experimentally verified using lysine specific chemical modifications and A beta fibrils mutated at Asn27 We found that both Congo red and Myricetin, despite being structurally different, bound at the same two sites Additionally, our data suggests that three additional A beta toxicity inhibitors may also bind in one of the sites Identification of these common binding loci provides targets on the A beta fibril surface that can be tested in the future for their role in A beta biological activity