Cryo-EM structures of amyloid-β 42 filaments from human brains

Science. 2022 Jan 14;375(6577):167-172. doi: 10.1126/science.abm7285. Epub 2022 Jan 13.

Abstract

Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Amino Acid Sequence
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / ultrastructure*
  • Animals
  • Brain Chemistry*
  • Cryoelectron Microscopy
  • Female
  • Gene Knock-In Techniques
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Models, Animal
  • Models, Molecular
  • Peptide Fragments / chemistry*
  • Peptide Fragments / genetics
  • Peptide Fragments / ultrastructure*
  • Protein Conformation
  • Protein Conformation, beta-Strand
  • Protein Domains
  • Protein Folding

Substances

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