A structural model for Alzheimer's β-amyloid fibrils based on experimental constraints from solid state NMR

TLDR

The study presents a structural model of Abeta(1‑40) amyloid fibrils derived from solid‑state NMR constraints. The model incorporates cross‑beta motifs from X‑ray diffraction and satisfies fibril dimensional and mass‑per‑length constraints from electron microscopy. The model shows that residues 12–24 and 30–40 form parallel beta‑sheets, residues 25–29 bend to connect them, creating a double‑layered cross‑beta unit with a hydrophobic core stabilized by D23–K28 salt bridges, while the first 10 residues remain disordered and minimal fibrils comprise two such units with juxtaposed hydrophobic faces.

Abstract

We present a structural model for amyloid fibrils formed by the 40-residue beta-amyloid peptide associated with Alzheimer's disease (Abeta(1-40)), based on a set of experimental constraints from solid state NMR spectroscopy. The model additionally incorporates the cross-beta structural motif established by x-ray fiber diffraction and satisfies constraints on Abeta(1-40) fibril dimensions and mass-per-length determined from electron microscopy. Approximately the first 10 residues of Abeta(1-40) are structurally disordered in the fibrils. Residues 12-24 and 30-40 adopt beta-strand conformations and form parallel beta-sheets through intermolecular hydrogen bonding. Residues 25-29 contain a bend of the peptide backbone that brings the two beta-sheets in contact through sidechain-sidechain interactions. A single cross-beta unit is then a double-layered beta-sheet structure with a hydrophobic core and one hydrophobic face. The only charged sidechains in the core are those of D23 and K28, which form salt bridges. Fibrils with minimum mass-per-length and diameter consist of two cross-beta units with their hydrophobic faces juxtaposed.