Title: Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta(42) to Abeta(40) ratio
Authors: Kuperstein, Inna ×
Broersen, Kerensa
Benilova, Iryna
Rozenski, Jef
Jonckheere, Wim
Debulpaep, Maja
Vandersteen, Annelies
Segers-Nolten, Ine
Van Der Werf, Kees
Subramaniam, Vinod
Braeken, Dries
Callewaert, Geert
Bartic, Carmen
D'Hooge, Rudi
Martins, Ivo Cristiano
Rousseau, Frederic
Schymkowitz, Joost
De Strooper, Bart #
Issue Date: Oct-2010
Publisher: Nature Publishing Group
Series Title: EMBO Journal vol:29 issue:19 pages:3408-3420
Abstract: The amyloid peptides Abeta(40) and Abeta(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although Abeta(42) seems more pathogenic than Abeta(40), the reason for this is not well understood. We show here that small alterations in the Abeta(42):Abeta(40) ratio dramatically affect the biophysical and biological properties of the Abeta 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 Abeta(42):Abeta(40) ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Abeta species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Abeta 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.
ISSN: 0261-4189
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry (Rega Institute)
Laboratory for the Research of Neurodegenerative Diseases
Solid State Physics and Magnetism Section
Laboratory for Biological Psychology
Laboratory of Molecular and Cellular Signaling
Department of Human Genetics - miscellaneous
Physiology Section (-)
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