Neurotoxicity of Alzheimer’s disease Ab peptides is induced by small changes in the Ab42 to Ab40 ratio

The amyloid peptides Ab40 and Ab42 of Alzheimer’s disease are thought to contribute differentially to the disease process. Although Ab42 seems more pathogenic than Ab40, the reason for this is not well understood. We show here that small alterations in the Ab42:Ab40 ratio dramatically affect the biophysical and biological proper-ties of the Ab 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 Ab42:Ab40 ratio stabilizes toxic oligomeric species with intermediate conformations. The initial toxic impact of these Ab species is synaptic in nature, but this can spread into the cells leading to neuronal cell death. The fact that the relative ratio of Ab peptides is more crucial than the absolute amounts of peptides for th