title: Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.
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 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.
authors.affiliation: Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
authors.forename: Inna
authors.initials: I
authors.lastname: Kuperstein
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Wim
authors.initials: W
authors.lastname: Jonckheere
authors.forename: Maja
authors.initials: M
authors.lastname: Debulpaep
authors.forename: Annelies
authors.initials: A
authors.lastname: Vandersteen
authors.forename: Ine
authors.initials: I
authors.lastname: Segers-Nolten
authors.forename: Kees
authors.initials: K
authors.lastname: Van Der Werf
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
authors.forename: Dries
authors.initials: D
authors.lastname: Braeken
authors.forename: Geert
authors.initials: G
authors.lastname: Callewaert
authors.forename: Carmen
authors.initials: C
authors.lastname: Bartic
authors.forename: Rudi
authors.initials: R
authors.lastname: D'Hooge
authors.forename: Ivo Cristiano
authors.initials: IC
authors.lastname: Martins
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000704:Analysis of Variance; D000818:Animals; D052160:Benzothiazoles; D001703:Biophysics; D005456:Fluorescent Dyes; D006801:Humans; D007700:Kinetics; D051379:Mice; D008839:Microelectrodes; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000378:metabolism*; D011485:Protein Binding; D017550:Spectroscopy, Fourier Transform Infrared; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009462:thioflavin T
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