CNRS UMR 5089, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, Toulouse, France.
Chembiochem. 2010 Jan 4;11(1):110-8. doi: 10.1002/cbic.200900474.
Amyloid-beta peptides (Abeta) and the protein human serum albumin (HSA) interact in vivo. They are both localised in the blood plasma and in the cerebrospinal fluid. Among other functions, HSA is involved in the transport of the essential metal copper. Complexes between Abeta and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer's disease, where Cu is involved in Abeta aggregation and production of reactive oxygen species (ROS). In the present work, we studied copper-exchange reaction between Abeta and HSA or the tetrapeptide DAHK (N-terminal Cu-binding domain of HSA) and the consequence of this exchange on Abeta-induced ROS production and cell toxicity. The following results were obtained: 1) HSA and DAHK removed Cu(II) from Abeta rapidly and stoichiometrically, 2) HSA and DAHK were able to decrease Cu-induced aggregation of Abeta, 3) HSA and DAHK suppressed the catalytic HO(.) production in vitro and ROS production in neuroblastoma cells generated by Cu-Abeta and ascorbate, 4) HSA and DAHK were able to rescue these cells from the toxicity of Cu-Abeta with ascorbate, 5) DAHK was more potent in ROS suppression and restoration of neuroblastoma cell viability than HSA, in correlation with an easier reduction of Cu(II)-HSA than Cu-DAHK by ascorbate, in vitro. Our data suggest that HSA is able to decrease aberrant Cu(II)-Abeta interaction. The repercussion of the competition between HSA and Abeta to bind Cu in the blood and brain and its relation to Alzheimer's disease are discussed.
淀粉样β肽（Abeta）和人血清白蛋白（HSA）在体内相互作用。它们都定位于血浆和脑脊液中。除其他功能外，HSA 还参与必需金属铜的运输。已经提出 Abeta 与铜离子之间的复合物是一种异常相互作用，与阿尔茨海默病的发展有关，其中 Cu 参与 Abeta 聚集和活性氧（ROS）的产生。在本工作中，我们研究了 Abeta 与人血清白蛋白（HSA）或四肽 DAHK（HSA 的 N 端 Cu 结合结构域）之间的铜交换反应，以及这种交换对 Abeta 诱导的 ROS 产生和细胞毒性的影响。得到以下结果：1）HSA 和 DAHK 从 Abeta 中快速且定量地去除 Cu(II)，2）HSA 和 DAHK 能够降低 Cu 诱导的 Abeta 聚集，3）HSA 和 DAHK 抑制了体外 HO(.)产生和 Cu-Abeta 和抗坏血酸产生的神经母细胞瘤细胞中的 ROS 产生，4）HSA 和 DAHK 能够挽救这些细胞免受 Cu-Abeta 和抗坏血酸引起的毒性，5）DAHK 在 ROS 抑制和神经母细胞瘤细胞活力恢复方面比 HSA 更有效，这与体外抗坏血酸更容易还原 Cu(II)-HSA 而不是 Cu-DAHK 有关。我们的数据表明，HSA 能够降低异常的 Cu(II)-Abeta 相互作用。讨论了 HSA 与 Abeta 竞争结合血液和大脑中 Cu 的相互作用及其与阿尔茨海默病的关系。
