Journal
EMBO JOURNAL
Volume 29, Issue 19, Pages 3408-3420Publisher
WILEY
DOI: 10.1038/emboj.2010.211
Keywords
Alzheimer's disease; beta-amyloid peptides; microelectrode array; neurotoxicity; oligomer
Categories
Funding
- Fund for Scientific Research, Flanders
- Artificial SynApse (IWT ASAP)
- Federal Office for Scientific Affairs, Belgium [IUAP P6/43]
- KULeuven
- Flemish Government
- European Union [F2-2007-200611]
- FWO
- Alzheimer Research Trust (ART) UK
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The amyloid peptides A beta(40) and A beta(42) of Alzheimer's disease are thought to contribute differentially to the disease process. Although A beta(42) seems more pathogenic than A beta(40), the reason for this is not well understood. We show here that small alterations in the A beta(42):A beta(40) ratio dramatically affect the biophysical and biological properties of the A beta 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 A beta(42):A beta(40) ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these A beta species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of A beta 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. The EMBO Journal (2010) 29, 3408-3420. doi:10.1038/emboj.2010.211; Published online 3 September 2010
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