期刊
SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-33935-5
关键词
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资金
- China Scholarship Council
- BBSRC [BB/M023877/1]
- BBSRC [BB/M023877/1] Funding Source: UKRI
Oxidative stress and the formation of plaques which contain amyloid-beta (A beta) peptides are two key hallmarks of Alzheimer's disease (AD). Dityrosine is found in the plaques of AD patients and A beta dimers have been linked to neurotoxicity. Here we investigate the formation of A beta dityrosine dimers promoted by Cu2+/+ Fenton reactions. Using fluorescence measurements and UV absorbance, we show that dityrosine can be formed aerobically when A beta 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 beta. We show that oxidative modification of A beta impedes the ability for A beta 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 beta(1-40). Importantly, the addition of Cu2+ and a reductant to preformed A beta(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 beta fibres, dimer formation, and fibre fragmentation within plaques are likely to have a significant impact on A beta clearance and neurotoxicity.
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