Guilloreau Luc, Combalbert Sarah, Sournia-Saquet Alix, Mazarguil Honoré, Faller Peter
Laboratoire de Chimie de Coordination, CNRS UPR 8241 associated with the University of Toulouse III, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
Chembiochem. 2007 Jul 23;8(11):1317-25. doi: 10.1002/cbic.200700111.
Aggregation of the beta-amyloid peptide (Abeta) to amyloid plaques is a key event in Alzheimer's disease. According to the amyloid-cascade hypothesis, Abeta aggregates are toxic to neurons through the production of reactive oxygen species (ROS). Copper ions play an important role, because they are able to bind to Abeta and influence its aggregation properties. Moreover, Cu-Abeta is supposed to be directly involved in ROS production. To get a better understanding of these reactions, we measured the production of HO(.) and the redox potential of Cu-Abeta. The results were compared to other biological copper-peptide complexes in order to get an insight into the biological relevance. Cu-Abeta produced more HO(.) than the complex of copper with Asp-Ala-His-Lys (Cu-DAHK), but less than with Gly-His-Lys (Cu-GHK). Cyclic voltammetry revealed that the order for reduction potential is Cu-GHK>Cu-Abeta>Cu-DAHK, but for the oxidation potential the order is reversed. Thus, easier copper redox cycling correlated to higher HO(.) production. The copper complex of the form Abeta1-42 showed a HO(.) production five-times higher than that of the form Abeta1-40. Time-dependence and aggregation studies suggest that an aggregation intermediate is responsible for this increased HO(.) production.
β-淀粉样肽（Aβ）聚集成淀粉样斑块是阿尔茨海默病中的关键事件。根据淀粉样蛋白级联假说，Aβ聚集体通过产生活性氧（ROS）对神经元有毒性作用。铜离子起着重要作用，因为它们能够与Aβ结合并影响其聚集特性。此外，铜-Aβ被认为直接参与ROS的产生。为了更好地理解这些反应，我们测量了羟基自由基（HO(.)）的产生以及铜-Aβ的氧化还原电位。将结果与其他生物铜肽复合物进行比较，以便深入了解其生物学相关性。铜-Aβ产生的HO(.)比铜与天冬氨酸-丙氨酸-组氨酸-赖氨酸形成的复合物（铜-DAHK）更多，但比与甘氨酸-组氨酸-赖氨酸形成的复合物（铜-GHK）少。循环伏安法显示，还原电位的顺序为铜-GHK>铜-Aβ>铜-DAHK，但氧化电位的顺序相反。因此，更容易的铜氧化还原循环与更高的HO(.)产生相关。Aβ1-42形式的铜复合物产生的HO(.)比Aβ1-40形式高五倍。时间依赖性和聚集研究表明，一种聚集中间体是这种HO(.)产生增加的原因。
