Linking folding with aggregation in Alzheimer's β-amyloid peptides

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Abstract
Growing evidence suggests that the beta-amyloid (Abeta) peptides of Alzheimer's disease are generated in early endosomes and that small oligomers are the principal toxic species. We sought to understand whether and how the solution pH, which is more acidic in endosomes than the extracellular environment, affects the conformational processes of Abeta. Using constant pH molecular dynamics simulations of two model peptides, Abeta(1-28) and Abeta(10-42), we found that the folding landscape of Abeta is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that Abeta oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.