pH Dependence of Amyloid-ß Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes.

ABSTRACT

Central to Alzheimer's disease (AD) is the assembly of the amyloid-beta peptide (Aß) into fibrils. A reduction in pH accompanying inflammation or subcellular compartments, may accelerate fibril formation as the pH approaches Aß's isoelectric point (pI). Using global fitting of fibril formation kinetics over a range of pHs, we identify the impact net charge has on individual fibril assembly microscopic rate constants. We show that the primary nucleation has a strong pH dependence. The titration behaviour exhibits a mid-point or pKa of 7.0, close to the pKa of Aß histidine imidazoles. Surprisingly, both the secondary nucleation and elongation rate constants are pH independent. This indicates the charge of Aß, in particular histidine protonation, has little impact on this stage of Aß assembly. These fundamental processes are key to understanding the forces that drive the assembly of Aß into toxic oligomers and fibrils.