3D structure of Alzheimer's amyloid-β(1-42) fibrils

Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (A beta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising A beta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta 1) and 31-42 (beta 2). At least two molecules of A beta(1-42) are required to achieve the repeating structure of a protofilament. intermolecular side-chain contacts are formed between the odd-numbered residues of strand 131 of the nth molecule and the even-numbered residues of strand beta 2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of A beta fibril growth. It also provides a structural basis for fibrillization inhibitors.