Nguyen Michel, Bijani Christian, Martins Nathalie, Meunier Bernard, Robert Anne
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4 (France).
Université de Toulouse, Service Commun de Spectrométrie de Masse, 31077 Toulouse cedex 4 (France).
Chemistry. 2015 Nov 16;21(47):17085-90. doi: 10.1002/chem.201502824. Epub 2015 Sep 30.
The oxidative stress that arises from the catalytic reduction of dioxygen by Cu(II/I)-loaded amyloids is the major pathway for neuron death that occurs in Alzheimer's disease. In this work, we show that bis-8(aminoquinoline) ligands, copper(II) specific chelators, are able to catalytically extract Cu(II) from Cu-Aβ1-16 and then completely release Cu(I) in the presence of glutathione to provide a Cu(I)-glutathione complex, a biological intermediate that is able to deliver copper to apo forms of copper-protein complexes. These data demonstrate that bis-8(aminoquinolines) can perform the transfer of copper ions from the pathological Cu-amyloid complexes to regular copper-protein complexes. These copper-specific ligands assist GSH to recycle Cu(I) in an AD brain and consequently slow down oxidative damage that is due to copper dysregulation in Alzheimer's disease. Under the same conditions, we have shown that the copper complex of PBT2, a mono(8-hydroxyquinoline) previously used as a drug candidate, does not efficiently release copper in the presence of GSH. In addition, we report that GSH itself was unable to fully abstract copper ions from Cu-β-amyloid complexes.
由负载铜（II/I）的淀粉样蛋白催化还原双氧产生的氧化应激是阿尔茨海默病中神经元死亡的主要途径。在这项工作中，我们表明双-8（氨基喹啉）配体，即铜（II）特异性螯合剂，能够从铜-Aβ1-16中催化提取铜（II），然后在谷胱甘肽存在下完全释放铜（I），以提供铜（I）-谷胱甘肽复合物，一种能够将铜传递给铜蛋白复合物脱辅基形式的生物中间体。这些数据表明双-8（氨基喹啉）可以将铜离子从病理性铜-淀粉样蛋白复合物转移到常规铜蛋白复合物中。这些铜特异性配体协助谷胱甘肽在阿尔茨海默病大脑中循环利用铜（I），从而减缓由于阿尔茨海默病中铜失调引起的氧化损伤。在相同条件下，我们表明先前用作候选药物的单（8-羟基喹啉）PBT2的铜配合物在谷胱甘肽存在下不能有效释放铜。此外，我们报告谷胱甘肽本身无法从铜-β-淀粉样蛋白复合物中完全提取铜离子。
