The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils

Stewart R. Durell, Rakez Kayed, H. Robert Guy

Research output: Contribution to journalArticlepeer-review

Abstract

Amyloid beta (Aβ) peptides are a major contributor to Alzheimer's disease. They occur in differing lengths, each of which forms a multitude of assembly types. The most toxic soluble oligomers are formed by Aβ42; some of which have antiparallel β-sheets. Previously, our group proposed molecular models of Aβ42 hexamers in which the C-terminus third of the peptide (S3) forms an antiparallel 6-stranded β-barrel that is surrounded by an antiparallel barrel formed by the more polar N-terminus (S1) and middle (S2) portions. These hexamers were proposed to act as seeds from which dodecamers, octadecamers, both smooth annular protofibrils (sAPFs) and beaded annular protofibrils (bAPFs), and transmembrane channels form. Since then, numerous aspects of our models have been supported by experimental findings. Recently, NMR-based structures have been proposed for Aβ42 tetramers and octamers, and NMR studies have been reported for oligomers composed of ~32 monomers. Here we propose a range of concentric β-barrel models and compare their dimensions to image-averaged electron micrographs of both bAPFs and sAPFs of Aβ42. The smaller oligomers have 6, 8, 12, 16, and 18 monomers. These beads string together to form necklace-like bAPFs. These bAPRs gradually morph into sAPFs in which a S3 β-barrel is shielded on one or both sides by β-barrels formed from S1 and S2 segments.

Original languageEnglish (US)
Pages (from-to)1190-1209
Number of pages20
JournalProteins: Structure, Function and Bioinformatics
Volume90
Issue number5
DOIs
StatePublished - May 2022
Externally publishedYes

Keywords

  • amyloid beta 42
  • amyloids
  • annular protofibrils
  • concentric β-barrels
  • oligomers
  • structural models

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Fingerprint

Dive into the research topics of 'The amyloid concentric β-barrel hypothesis: Models of amyloid beta 42 oligomers and annular protofibrils'. Together they form a unique fingerprint.

Cite this