Beschreibung:
<p> Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-β (Aβ) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Aβ(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 β-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a β-strand-turn-β-strand motif that contains two intermolecular, parallel, in-register β-sheets that are formed by residues 18-26 (β1) and 31-42 (β2). At least two molecules of Aβ(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 β1 of the nth molecule and the even-numbered residues of strand β2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired β-strands at the f ibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Aβ fibril growth. It also provides a structural basis for fibrillization inhibitors. </p>