Nitration of amyloid-beta peptide (1-42) as a protective mechanism for the amyloid-beta peptide (1-42) against copper ion toxicity
Nitration of amyloid-beta peptide (1-42) as a protective mechanism for the amyloid-beta peptide (1-42) against copper ion toxicity
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淀粉样β肽 (1-42) 的硝化作为淀粉样β肽 (1-42) 对抗铜离子毒性的保护机制
DOI：
10.1016/j.jinorgbio.2018.10.005
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发表时间：
2019
影响因子：
3.9
通讯作者：
Gao Zhonghong
中科院分区：
文献类型：
--
作者：
Zhao Jie;Gao Wanxia;Yang Zhen;Li Hailing;Gao Zhonghong
众所周知，铜离子（Cu(II)）与淀粉样蛋白-β肽（Aβ）结合，诱导Aβ寡聚物形成，最终加剧阿尔茨海默病（AD）中Aβ聚集的神经毒性。这种化学修饰如何影响Aβ和Cu（II）的相互作用以及它们在AD发展中的作用变得很有趣。在这项工作中，我们研究了a β1 - 42硝化与有毒Cu（II）的相互作用。结果表明，在亚硝酸盐和过氧化氢存在下，Cu（II）诱导a β1 - 42硝化。圆二色性研究还发现，a β 1-42和Tyr10硝化淀粉样蛋白-β肽（1-42）（Aβ1-42NT）在与Cu（II）相互作用时发生了显著的构象变化。虽然硝化作用没有改变a - β1 - 42与Cu（II）的结合，也没有改变a - β1 - 42-Cu（II）复合物的过氧化活性，但硝化作用改善了Cu（II）诱导的a - β1 - 42的聚集和神经毒性，细胞研究也进一步证实了这一点。鉴于我们之前的研究结果，Aβ硝化可以显著抑制其聚集，从而降低其毒性，我们推测Aβ1 - 42的硝化可以改变其分子间相互作用，从而保护其免受Cu（II）的毒性。基于这一假设，我们认为a - β1 - 42的硝化作用可能是a - β1 - 42正常功能的重要保护机制，在AD药物开发中值得关注。
It is known that copper ion (Cu(II)) binds to amyloid-β peptide (Aβ), induces Aβ oligomer formation and ultimately exacerbates Aβ-aggregation neurotoxicity in Alzheimer's disease (AD). It becomes interesting to know that how this chemical modification of Aβ would affect interaction of Aβ and Cu(II) and their roles in the development of AD. In this work, we investigated the interaction of Aβ1–42nitration with the toxic Cu(II). It showed that Cu(II)induced Aβ1–42nitration in the presence of nitrite and hydrogen peroxide. Circular dichroism studies also revealed significant conformational change of Aβ1–42and Tyr10 nitrated amyloid-β peptide(1–42) (Aβ1–42NT) when interacting with Cu(II). Even though nitration did not alter the binding of Aβ1–42to Cu(II) or the peroxidative activity of Aβ1–42-Cu(II) complex, nitration ameliorated the aggregation and neurotoxicity of Aβ1–42induced by Cu(II), which was also further confirmed by the cell study. Given our previous findings that Aβ nitration dramatically inhibited its aggregation and thus reduced its toxicity, we speculated that nitration of Aβ1–42altered its intermolecular interaction, which protected itself against the toxicity of Cu(II). Based on this hypothesis, we propose that nitration of Aβ1–42may be an important protective mechanism for normal function of Aβ1–42and deserves more attention in AD drug development.