Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool

J Biol Chem. 2012 Oct 26;287(44):36732-43. doi: 10.1074/jbc.M112.394635. Epub 2012 Sep 19.


Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ(1-38) and Aβ(1-40) at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ(1-38) and Aβ(1-43) in addition to Aβ(1-40) and Aβ(1-42), in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ(1-38) and Aβ(1-43) aggregate similar to Aβ(1-40) and Aβ(1-42), respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ(1-38) and Aβ(1-43) significantly affect the behaviors of Aβ(1-40) and Aβ(1-42). The short timescale conformational flexibility of Aβ(1-38) is suggested to be responsible for enhancing toxicity of Aβ(1-40) while exerting a cyto-protective effect on Aβ(1-42). Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amino Acid Motifs
  • Amyloid / pharmacology
  • Amyloid / physiology*
  • Amyloid / ultrastructure
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / pharmacology
  • Amyloid beta-Peptides / physiology
  • Benzothiazoles
  • Cell Line
  • Cell Survival / drug effects
  • Fluorescent Dyes / chemistry
  • Humans
  • Kinetics
  • Microscopy, Atomic Force
  • Peptide Fragments / chemistry*
  • Peptide Fragments / pharmacology
  • Peptide Fragments / physiology
  • Protein Multimerization*
  • Protein Structure, Quaternary
  • Thiazoles / chemistry


  • Amyloid
  • Amyloid beta-Peptides
  • Benzothiazoles
  • Fluorescent Dyes
  • Peptide Fragments
  • Thiazoles
  • thioflavin T