PH Dependence of Amyloid-β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes.

ABSTRACT: Central to Alzheimer's disease (AD) is the assembly of the amyloid-beta peptide (Aβ) into fibrils. A reduction in pH accompanying inflammation or subcellular compartments, may accelerate fibril formation as the pH approaches Aβ'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 pK_a of 7.0, close to the pK_a of Aβ histidine imidazoles. Surprisingly, both the secondary nucleation and elongation rate constants are pH independent. This indicates the charge of Aβ, in particular histidine protonation, has little impact on thi

SUBMITTER: Tian Y 

PROVIDER: S-EPMC9828734 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature