Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-beta (A beta) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar A beta assemblies is accompanied by a conformational change toward a high content of beta-structure. Here, we report the solution structure of A beta(1-40) in complex with the phage-display selected affibody protein Z(A1 beta 3), a binding protein of nanomolar affinity. Bound A beta(1-40) features a beta-hairpin comprising residues 17-36, providing the first high-resolution structure of A beta in beta conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar A beta. Z(A beta 3) stabilizes the beta-sheet by extending it inter-molecularly and by burying both of the mostly nonpolar faces of the A beta hairpin within a large hydrophobic tunnel-like cavity. Consequently, Z(A beta 3) acts as a stoichiometric inhibitor of A beta fibrillation. The selected A beta conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.