Linking folding with aggregation in Alzheimer's beta-amyloid peptides.

Growing evidence suggests that the β-amyloid (Aβ) 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 Aβ. Using constant pH molecular dynamics simulations of two model peptides, Aβ(1–28) and Aβ(10–42), we found that the folding landscape of Aβ is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that Aβ oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.