Copper Redox Cycling Inhibits A? Fibre Formation and Promotes Fibre Fragmentation, while Generating a Dityrosine A? Dimer.

ABSTRACT: Oxidative stress and the formation of plaques which contain amyloid-? (A?) peptides are two key hallmarks of Alzheimer's disease (AD). Dityrosine is found in the plaques of AD patients and A? dimers have been linked to neurotoxicity. Here we investigate the formation of A? dityrosine dimers promoted by Cu^2+/+ Fenton reactions. Using fluorescence measurements and UV absorbance, we show that dityrosine can be formed aerobically when A? is incubated with Cu²⁺ and hydrogen-peroxide_, or in a Cu²⁺ and ascorbate redox mixture. The dityrosine cross-linking can occur for both monomeric and fibrillar forms of A?. We show that oxidative modification of A? impedes the ability for A? monomer to form fibres, as indicated by the amyloid specific dye Thioflavin T (ThT). Transmission electron microscopy (TEM) indicates the limited amyloid assemblies that form have a marked reduction in fibre length for A?(1-40). Importantly, the addition of Cu²⁺ and a reductant to preformed A?(1-40) fibers causes their widespread fragmentation, reducing median fibre lengths from 800?nm to 150?nm upon oxidation. The processes of covalent cross-linking of A? fibres, dimer formation, and fibre fragmentation within plaques are likely to have a significant impact on A? clearance and neurotoxicity.

SUBMITTER: Gu M 

PROVIDER: S-EPMC6212427 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature