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

Inna Kuperstein, Kerensa Broersen, Iryna Benilova, Jef Rozenski, Wim Jonckheere, Maja Debulpaep, Annelies Vandersteen, Ine Segers-Nolten, Kees van der Werf, Vinod Subramaniam, Dries Braeken, Geert Callewaert, Carmen Bartic, Rudi D'Hooge, Ivo Cristiano Martins, Frederic Rousseau, Joost Schymkowitz, Bart De Strooper

    Research output: Contribution to JournalArticleAcademicpeer-review


    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.

    Original languageEnglish
    Pages (from-to)3408-20
    Number of pages13
    JournalEMBO Journal
    Issue number19
    Publication statusPublished - 6 Oct 2010


    • Alzheimer Disease
    • Amyloid beta-Peptides
    • Analysis of Variance
    • Animals
    • Biophysics
    • Fluorescent Dyes
    • Humans
    • Kinetics
    • Mice
    • Microelectrodes
    • Microscopy, Electron, Transmission
    • Neurons
    • Patch-Clamp Techniques
    • Peptide Fragments
    • Plaque, Amyloid
    • Protein Binding
    • Spectroscopy, Fourier Transform Infrared
    • Thiazoles
    • Journal Article
    • Research Support, Non-U.S. Gov't


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