Electrochemical and Conformational Consequences of Copper (CuI and CuII) Binding to β-Amyloid(1-40)
Electrochemical and Conformational Consequences of Copper (CuI and CuII) Binding to β-Amyloid(1-40)
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DOI：
10.1002/cbic.200800732
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发表时间：
2009-04-14
期刊：
影响因子：
3.2
通讯作者：
Elbaum, Danek
中科院分区：
文献类型：
--
作者：
Brzyska, Maria;Trzesniewska, Katarzyna;Elbaum, Danek
β-淀粉样蛋白 (Aβ) 细胞外沉积到老年斑中是在阿尔茨海默病 (AD) 患者大脑中观察到的主要特征。高浓度的铜与不溶性淀粉样斑块有关。众所周知，A beta(1-40) 可以以高亲和力结合铜，但 A beta(1-40)-Cu 配合物的电化学性质尚未得到很好的表征。在本研究中，我们证明 A beta(1-40) 与铜（Cu-I 和 Cu-II 形式）的络合会降低金属电化学活性。铜-A beta(1-40) 复合物的形成与氧化还原电位的改变有关。数据揭示了新鲜 A β-铜溶液的显着氧化还原活性。然而，CD 记录的铜诱导的肽结构重排与复合物形式还原电位 (E-0') 随时间的变化相对应。荧光和电化学（循环伏安法和微分脉冲伏安法）技术表明，Aβ-Cu 配合物氧化还原活性的降低可能是由于构象变化减少了铜与外部环境的可及性。根据我们的证据，铜与淀粉样蛋白结合诱导的构象重排延长了获得与不含金属的肽相同的 P-折叠含量所需的时间。尽管 Aβ-Cu 复合物的氧化还原活性会随时间而减弱，但它们并非完全没有毒性，因为即使在长时间孵育后，它们也会破坏红细胞渗透脆性的稳定性。
Extracellular deposits of beta-amyloid (A beta) into senile plaques are the major features observed in brains of Alzheimer's disease (AD) patients. A high concentration of copper has been associated with insoluble amyloid plaques. It is known that A beta(1-40) can bind copper with high affinity, but electrochemical properties of A beta(1-40)-Cu complexes are not well-characterised. In this study we demonstrate that complexation of copper (both as Cu-I and Cu-II) by A beta(1-40) reduces the metal electrochemical activity. Formation of copper-A beta(1-40) complexes is associated with alteration of the redox potential. The data reveal significant redox activity of fresh A beta-copper solutions. However, copper-induced structural rearrangements of the peptide, documented by CD, correspond with time-dependent changes of formal reduction potentials (E-0') of the complex. Fluorescent and electrochemical (cyclic voltammetry and differential pulse voltammetry) techniques suggest that reduction of the redox activity by A beta-Cu complexes could be attributed to conformational changes that diminished copper accessibility to the external environment. According to our evidence, conformational rearrangements, induced by copper binding to amyloid, elongate the time necessary to attain the same P-sheet content as for the metal-free peptide. Although the redox activity of A beta-Cu complexes diminishes in a time-dependent manner, they are not completely devoid of toxicity as they destabilize red blood cells osmotic fragility, even after prolonged incubation.