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

TLDR

Alzheimer’s disease is the most fatal neurodegenerative disorder, with amyloid‑β amyloidogenesis appearing causative. The study presents the 3D structure of Aβ(1–42) fibrils. The structure was determined using hydrogen‑bonding constraints from quenched H/D‑exchange NMR, side‑chain packing constraints from pairwise mutagenesis, and solid‑state NMR data, revealing that at least two Aβ(1–42) molecules are required for the protofilament repeat. The structure shows residues 18–42 form a β‑strand–turn–β‑strand motif with two parallel in‑register β‑sheets, and inter‑molecular side‑chain contacts between odd β1 residues and even β2 residues create partially unpaired strands at fibril ends, explaining growth properties and offering a basis for inhibitors.

Abstract

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 n th 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 fibrillar 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.