Copper Transfer from Cu-Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity
Copper Transfer from Cu-Aβ to Human Serum Albumin Inhibits Aggregation, Radical Production and Reduces Aβ Toxicity
复制标题
DOI：
10.1002/cbic.200900474
复制
发表时间：
2010-01-04
期刊：
影响因子：
3.2
通讯作者：
Faller, Peter
中科院分区：
文献类型：
--
作者：
Perrone, Lorena;Mothes, Emmanuelle;Faller, Peter
淀粉样β肽（A β）和蛋白质人血清白蛋白（HSA）在体内相互作用。它们都位于血浆和脑脊液中。在其他功能中，HSA参与运输必需的金属铜。已经提出A β和铜离子之间的络合物是与阿尔茨海默病的发展有关的异常相互作用，其中Cu参与A β聚集和活性氧物质（ROS）的产生。在本工作中，我们研究了A β与HSA或四肽DAHK（HSA的N-末端Cu结合结构域）之间的铜交换反应以及这种交换对A β诱导的ROS产生和细胞毒性的影响。获得了以下结果：1）HSA和DAHK快速且化学计量地从A β中去除Cu-II，2）HSA和DAHK能够减少Cu诱导的A β聚集，3）HSA和DAHK抑制体外催化HO中心点的产生和由Cu-A β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能够将这些细胞从Cu-A β与抗坏血酸盐的毒性中拯救出来。5）DAHK在ROS抑制和神经母细胞瘤细胞活力的恢复方面比HSA更有效，这与Cu-II-HSA比Cu-DAHK在体外更容易被抗坏血酸盐还原相关。我们的数据表明，HSA能够减少异常的Cu-II-A β相互作用。讨论了HSA与A β竞争结合血液和脑中Cu的反应及其与阿尔茨海默病的关系。
Amyloid-beta peptides (A beta) 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 A beta and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer's disease, where Cu is involved in A beta aggregation and production of reactive oxygen species (ROS). In the present work, we studied copper-exchange reaction between A beta and HSA or the tetrapepticle DAHK (N-terminal Cu-binding domain of HSA) and the consequence of this exchange on A beta-induced ROS production and cell toxicity. The following results were obtained: 1) HSA and DAHK removed Cu-II from A beta rapidly and stoichiometrically, 2) HSA and DAHK were able to decrease Cu-induced aggregation of A beta, 3) HSA and DAHK suppressed the catalytic HO center dot production in vitro and ROS production in neuroblastoma cells generated by Cu-A beta and ascorbate, 4) HSA and DAHK were able to rescue these cells from the toxicity of Cu-A beta 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-A beta interaction. The repercussion of the competition between HSA and A beta to bind Cu in the blood and brain and its relation to Alzheimer's disease are discussed.