Neurotoxicity of Alzheimer's disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio

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