Atomic-resolution structure of a disease-relevant Aβ(1-42) amyloid fibril

Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):E4976-84. doi: 10.1073/pnas.1600749113. Epub 2016 Jul 28.

Abstract

Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1-40) and Aβ(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1-42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-β-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.

Keywords: Alzheimer’s disease; amyloid; protein structure; solid-state NMR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / ultrastructure*
  • Cloning, Molecular
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Humans
  • Microscopy, Electron
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptide Fragments / genetics
  • Peptide Fragments / ultrastructure*
  • Protein Conformation, beta-Strand
  • Recombinant Proteins / genetics
  • Recombinant Proteins / ultrastructure

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Recombinant Proteins
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)

Associated data

  • PDB/2NAO