Oxidative stress and the formation of plaques which contain amyloid-β (Aβ) peptides are two key hallmarks of Alzheimer's disease (AD). Dityrosine is found in the plaques of AD patients and Aβ dimers have been linked to neurotoxicity. Here we investigate the formation of Aβ dityrosine dimers promoted by Cu^2+/+ Fenton reactions. Using fluorescence measurements and UV absorbance, we show that dityrosine can be formed aerobically when Aβ 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 Aβ. We show that oxidative modification of Aβ impedes the ability for Aβ 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 Aβ(1-40). Importantly, the addition of Cu²⁺ and a reductant to preformed Aβ(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 Aβ fibres, dimer formation, and fibre fragmentation within plaques are likely to have a significant impact on Aβ clearance and neurotoxicity.

中文翻译：

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铜氧化还原循环抑制Aβ纤维形成并促进纤维断裂，同时生成二酪氨酸Aβ二聚体。

氧化应激和含有淀粉样β（Aβ）肽的斑块的形成是阿尔茨海默氏病（AD）的两个关键标志。在AD患者的斑块中发现了二酪氨酸，Aβ二聚体与神经毒性有关。在这里，我们研究了由Cu ^{2 + / +} Fenton反应促进的Aβ二酪氨酸二聚体的形成。使用荧光测量和UV吸光度，我们表明当Aβ与铜孵育该dityrosine可以有氧形成²⁺和过氧化氢_，或在Cu ²⁺和抗坏血酸的氧化还原混合物。单体和原纤维形式的Aβ都可能发生二酪氨酸交联。我们显示，Aβ的氧化修饰会阻碍Aβ单体形成纤维的能力，如淀粉样蛋白特异性染料硫黄素T（ThT）所示。透射电子显微镜（TEM）表明形成的有限淀粉样蛋白组装物对于Aβ（1-40）具有明显的纤维长度减少。重要的是，向预制的Aβ（1-40）纤维中添加Cu ²⁺和还原剂会导致其广泛的破碎，从而使氧化后的中值纤维长度从800 nm减少至150 nm。Aβ纤维共价交联，二聚体形成和斑块内纤维断裂的过程可能会对Aβ清除率和神经毒性产生重大影响。