Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio

EMBO J. 2010 Oct 6;29(19):3408-20. doi: 10.1038/emboj.2010.211. Epub 2010 Sep 3.


The amyloid peptides Aβ(40) and Aβ(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although Aβ(42) seems more pathogenic than Aβ(40), the reason for this is not well understood. We show here that small alterations in the Aβ(42):Aβ(40) ratio dramatically affect the biophysical and biological properties of the Aβ mixtures reflected in their aggregation kinetics, the morphology of the resulting amyloid fibrils and synaptic function tested in vitro and in vivo. A minor increase in the Aβ(42):Aβ(40) ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Aβ species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Aβ peptides is more crucial than the absolute amounts of peptides for the induction of neurotoxic conformations has important implications for anti-amyloid therapy. Our work also suggests the dynamic nature of the equilibrium between toxic and non-toxic intermediates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Amyloid beta-Peptides / ultrastructure
  • Analysis of Variance
  • Animals
  • Benzothiazoles
  • Biophysics
  • Fluorescent Dyes
  • Humans
  • Kinetics
  • Mice
  • Microelectrodes
  • Microscopy, Electron, Transmission
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity*
  • Peptide Fragments / ultrastructure
  • Plaque, Amyloid / metabolism*
  • Protein Binding
  • Spectroscopy, Fourier Transform Infrared
  • Thiazoles


  • Amyloid beta-Peptides
  • Benzothiazoles
  • Fluorescent Dyes
  • Peptide Fragments
  • Thiazoles
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • thioflavin T