Copper Redox Cycling Inhibits Aβ Fibre Formation and Promotes Fibre Fragmentation, while Generating a Dityrosine Aβ Dimer.
Copper Redox Cycling Inhibits Aβ Fibre Formation and Promotes Fibre Fragmentation, while Generating a Dityrosine Aβ Dimer.
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DOI：
10.1038/s41598-018-33935-5
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发表时间：
2018-11-01
影响因子：
4.6
通讯作者：
Viles JH
中科院分区：
文献类型：
--
作者：
Gu M;Bode DC;Viles JH
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病（AD）的两个关键标志。在AD患者的斑块中发现了酪氨酸，并且Aβ二聚体与神经毒性有关。本文研究了Cu 2 +/+芬顿反应促进Aβ二酪氨酸二聚体的形成。使用荧光测量和紫外吸收，我们表明，当Aβ与Cu 2+和过氧化氢孵育时，或在Cu 2+和抗坏血酸氧化还原混合物中，可以有氧形成二酪氨酸。单体和纤维状Aβ均可发生双酪氨酸交联。我们发现，Aβ的氧化修饰阻碍了Aβ单体形成纤维的能力，如淀粉样蛋白特异性染料硫磺素T（ThT）所示。透射电子显微镜（TEM）显示，形成的有限淀粉样蛋白组装体具有Aβ（1-40）纤维长度的显著减少。重要的是，向预先形成的Aβ（1-40）纤维中加入Cu 2+和还原剂会导致它们广泛碎裂，在氧化后将中值纤维长度从800 nm减少到150 nm。斑块内Aβ纤维的共价交联、二聚体形成和纤维断裂过程可能对Aβ清除和神经毒性产生显著影响。
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 Cu2+/+ 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.
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DOI：
10.1039/c6mt00150e
发表时间：
2016-10-01
期刊：
Metallomics : integrated biometal science
影响因子：
--
作者：
Cheignon C;Faller P;Testemale D;Hureau C;Collin F
通讯作者：
Collin F
影响因子：
7.1
作者：
Al-Hilaly YK;Williams TL;Stewart-Parker M;Ford L;Skaria E;Cole M;Bucher WG;Morris KL;Sada AA;Thorpe JR;Serpell LC
通讯作者：
Serpell LC
DOI：
10.3109/13506129908993282
发表时间：
1999-03-01
期刊：
AMYLOID-INTERNATIONAL JOURNAL OF EXPERIMENTAL AND CLINICAL INVESTIGATION
影响因子：
--
作者：
Galeazzi, L;Ronchi, P;Giunta, S
通讯作者：
Giunta, S
DOI：
10.1016/j.bbapap.2010.04.001
发表时间：
2010-07
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Biancalana M;Koide S
通讯作者：
Koide S
影响因子：
15
作者：
Colvin MT;Silvers R;Frohm B;Su Y;Linse S;Griffin RG
通讯作者：
Griffin RG