Soluble amyloid β1-28-copper(I)/copper(II)/iron(II) complexes are potent antioxidants in cell-free systems
Soluble amyloid β1-28-copper(I)/copper(II)/iron(II) complexes are potent antioxidants in cell-free systems
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DOI：
10.1021/bi800114g
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发表时间：
2008-07-29
期刊：
影响因子：
2.9
通讯作者：
Fischer, Billia
中科院分区：
文献类型：
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作者：
Baruch-Suchodolsky, Rozena;Fischer, Billia
淀粉样蛋白β（A β）是阿尔茨海默病（AD）的主要特征。目前，关于A β金属离子（锌、铜和铁）配合物在AD发病机制中的作用存在长期争议。在这里，我们的目标是破译与AD和A β-金属离子络合物有关的氧化损伤之间的联系。为此，我们研究，使用ESR，调制Cu/Fe诱导的H2 O2分解的A β（1-28）（A β（28）），A β（40/42）的可溶性模型。在pH 6.6下，向含有100 μ M Cu（II）/Cu（I）/Fe（II）的0.6 nM-360 μ M A β（28）溶液中加入H2 O2，导致[中心点OH]的浓度依赖性S形衰减，IC 50值分别为61、59和84 μ M。此外，在Cu（I）-H2 O2体系中，A beta（28）在5 min内降低90%的中心点OH产生速率。与可溶性A beta（28）不同，A beta（28）-Cu聚集体表现出较差的抗氧化活性。可溶性A β（28）的抗氧化活性模式是双重的。主要（快速）机制涉及金属螯合，而次要（缓慢）机制涉及（OH）-O-中心点清除和Cu（Fe）-配位配体的氧化。根据我们的研究结果，我们提出可溶性A β可能在AD的早期阶段起保护作用，但在A β浓度为纳摩尔的健康个体中则不然。然而，当A β-金属离子络合物发生聚集时，它们显著失去其保护功能并允许发生氧化损伤。
Amyloid beta (A beta) is a central characteristic of Alzheimer's disease (AD). Currently, there is a long-standing dispute regarding the role of A beta-metal ion (Zn, Cu, and Fe) complexes in AD pathogenesis. Here, we aim to decipher the connection between oxidative damage implicated in AD and A beta-metal ion complexes. For this purpose we study, using ESR, the modulation of Cu/Fe-induced H2O2 decomposition by A beta(1-28) (A beta(28)), a soluble model of A beta(40/42). The addition of H2O2 to 0.6 nM-360 mu M A beta(28) solutions containing 100 mu M Cu(II)/Cu(I)/Fe(II) at pH 6.6 results in a concentration-dependent sigmoidal decay of [center dot OH] with IC50 values of 61, 59, and 84 mu M, respectively. Furthermore, A beta(28) reduces 90% of center dot OH production rate in the Cu(I)-H2O2 system in 5 min. Unlike soluble A beta(28), A beta(28)-Cu aggregates exhibit poor antioxidant activity. The mode of antioxidant activity of soluble A beta(28) is twofold. The primary (rapid) mechanism involves metal chelation, whereas the secondary (slow) mechanism involves (OH)-O-center dot scavenging and oxidation of Cu(Fe)-coordinating ligands. On the basis of our findings, we propose that soluble A beta may play a protective role in the early stages of AD, but not in healthy individuals, where A beta's concentration is nanomolar. Yet, when A beta-metal ion complexes undergo aggregation, they significantly lose their protective function and allow oxidative damage to occur.