Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio.
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.
Kuperstein
Inna
I
Department for Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
Broersen
Kerensa
K
Benilova
Iryna
I
Rozenski
Jef
J
Jonckheere
Wim
W
Debulpaep
Maja
M
Vandersteen
Annelies
A
Segers-Nolten
Ine
I
Van Der Werf
Kees
K
Subramaniam
Vinod
V
Braeken
Dries
D
Callewaert
Geert
G
Bartic
Carmen
C
D'Hooge
Rudi
R
Martins
Ivo Cristiano
IC
Rousseau
Frederic
F
Schymkowitz
Joost
J
De Strooper
Bart
B
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
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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