CNR - National Research Council of Italy , ICCOM - Institute for Chemistry of Organo-Metallic Compounds, via Madonna del Piano 10, I-50019 Sesto Fiorentino, Firenze, Italy.
J Phys Chem B. 2013 Dec 27;117(51):16455-67. doi: 10.1021/jp410046w. Epub 2013 Dec 13.
According to the amyloid cascade hypothesis, amyloid-β peptides (Aβ) play a causative role in Alzheimer's disease (AD), of which oligomeric forms are proposed to be the most neurotoxic by provoking oxidative stress. Copper ions seem to play an important role as they are bound to Aβ in amyloid plaques, a hallmark of AD. Moreover, Cu-Aβ complexes are able to catalyze the production of hydrogen peroxide and hydroxyl radicals, and oligomeric Cu-Aβ was reported to be more reactive. The flexibility of the unstructured Aβ peptide leads to the formation of a multitude of different forms of both Cu(I) and Cu(II) complexes. This raised the question of the structure-function relationship. We address this question for the biologically relevant Fenton-type reaction. Computational models for the Cu-Aβ complex in monomeric and dimeric forms were built, and their redox behavior was analyzed together with their reactivity with peroxide. A set of 16 configurations of Cu-Aβ was studied and the configurations were classified into 3 groups: (A) configurations that evolve into a linearly bound and nonreactive Cu(I) coordination; (B) reactive configurations without large reorganization between the two Cu redox states; and (C) reactive configurations with an open structure in the Cu(I)-Aβ coordination, which have high water accessibility to Cu. All the structures that showed high reactivity with H2O2 (to form HO(•)) fall into class C. This means that within all the possible configurations, only some pools are able to produce efficiently the deleterious HO(•), while the other pools are more inert. The characteristics of highly reactive configurations consist of a N-Cu(I)-N coordination with an angle far from 180° and high water crowding at the open side. This allows the side-on entrance of H2O2 and its cleavage to form a hydroxyl radical. Interestingly, the reactive Cu(I)-Aβ states originated mostly from the dimeric starting models, in agreement with the higher reactivity of oligomers. Our study gives a rationale for the Fenton-type reactivity of Cu-Aβ and how dimeric Cu-Aβ could lead to a higher reactivity. This opens a new therapeutic angle of attack against Cu-Aβ-based reactive oxygen species production.
根据淀粉样蛋白级联假说，淀粉样β肽（Aβ）在阿尔茨海默病（AD）中起致病作用，其中寡聚形式被认为通过引发氧化应激而具有最强的神经毒性。铜离子似乎起着重要作用，因为它们与 AD 标志性的淀粉样斑块中的 Aβ结合。此外，Cu-Aβ 配合物能够催化过氧化氢和羟基自由基的生成，并且报道寡聚 Cu-Aβ 更具反应性。无规卷曲的 Aβ 肽的灵活性导致形成多种不同形式的 Cu（I）和 Cu（II）配合物。这就提出了结构-功能关系的问题。我们针对生物学上相关的 Fenton 型反应来解决这个问题。构建了单体和二聚体形式的 Cu-Aβ 配合物的计算模型，并分析了它们的氧化还原行为及其与过氧化物的反应性。研究了 16 种 Cu-Aβ 配合物的构型，并将构型分为 3 组：（A）演变成线性结合且无反应性的 Cu（I）配位的构型；（B）在两个 Cu 氧化态之间没有大的重排的反应性构型；（C）Cu（I）-Aβ 配位中具有开放结构的反应性构型，其具有高水可及性到 Cu。所有与 H2O2（形成 HO(•)）具有高反应性的结构都属于 C 类。这意味着在所有可能的构型中，只有一些池能够有效地产生有害的 HO(•)，而其他池则更惰性。高反应性构型的特征是 N-Cu（I）-N 配位，角度远非 180°，并且在开口侧有高的水拥挤。这允许 H2O2 的侧入及其裂解形成羟基自由基。有趣的是，反应性 Cu（I）-Aβ 状态主要源自二聚体起始模型，这与寡聚体的更高反应性一致。我们的研究为 Cu-Aβ 的 Fenton 型反应性以及二聚体 Cu-Aβ 如何导致更高反应性提供了依据。这为针对 Cu-Aβ 基活性氧物质生成的新治疗靶点开辟了道路。
