Folding dynamics of Aβ42 monomer at pH 4.0–7.5 with and without physiological salt conditions – does the β1 or β2 region fold first?

Abstract

Amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Elucidating the seeding region and related context as well as their association can provide insight into the origins of misfolding, aggregation, and fibril growth and can subsequently increase our understanding of the mechanisms of pathology progression. To this end, we investigated the folding dynamics of Aβ42 monomer at pH 4.0–7.5 with/without physiological salt and predicted, for the first time, the subtle equilibrium between the seeding region (including charge and polarity of residues) of Aβ42 and the interaction context (pH and Na⁺/Cl⁻ ions). The solution acidity, number of positive/negative ions, and distribution of charged residues in each Aβ42 region jointly impact the seeding region and seeding rate. The association of these factors well reconciles the controversy regarding the optimal pH (5.0–5.5 or 6.0?) for Aβ42 to trigger seeding and whether the first seeding region is β1 or β2.