Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta(42) to Abeta(40) ratio

Inna Kuperstein, Kerensa Broersen, Kerensa Broersen, Iryna Benilova, Jef Rozenski, Wim Jonckheere, Gezina M.J. Segers-Nolten, Kees van der Werf, A. Vandersteen, Vinod Subramaniam

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Abstract

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 Aβ42:Aβ40 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 languageUndefined
Pages (from-to)3408-3420
Number of pages13
JournalEMBO journal
Volume29
Issue number19
DOIs
Publication statusPublished - 2010

Keywords

  • IR-80749
  • neurotoxicity
  • oligomer
  • microelectrode array
  • β-amyloid peptides
  • METIS-268280
  • Alzheimer's disease

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