Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, India 700032.
Inorg Chem. 2013 Feb 4;52(3):1318-27. doi: 10.1021/ic301865n. Epub 2013 Jan 18.
Alzheimer's disease (AD) patients show abnormally high concentrations of Cu(2+) in the amyloid β plaques. This invokes that Cu(2+) might play a crucial role in the onset of AD. The last few decades of research have also shown that Cu(2+) plays a significant role in the aggregation of Aβ plaques in the brain and the generation of oxidative stress. Because the crystal structures of Cu-Aβ are yet to be obtained, there are various proposed models for the Cu(2+) coordination environment of Aβ peptides. In this study, we have used the truncated hydrophilic part of the native Aβ peptide to probe the Cu(2+) coordination site of the peptide, using a combination of spectroscopy and exogenous ligand-binding studies. It is evident from our study that Aβ(1-16) binds 1 equiv of Cu(2+) and yet shows an equilibrium between two species with a pK(a) of ~8.1. Ligand-field analysis of absorption and circular dichroism spectroscopy data indicates five-coordinate geometry for both components. We investigate the effect of azide and 8-hydroxyquinoline binding to Cu-Aβ and demonstrate the presence of a water-derived ligand and a second exchangeable ligand coordinated to copper at physiological pH, along the equatorial plane of a square-pyramidal active site.
阿尔茨海默病（AD）患者的淀粉样β斑块中 Cu(2+)浓度异常升高。这表明 Cu(2+)可能在 AD 的发病机制中起关键作用。过去几十年的研究还表明，Cu(2+)在大脑中 Aβ斑块的聚集和氧化应激的产生中起着重要作用。由于尚未获得 Cu-Aβ的晶体结构，因此对于 Aβ肽的 Cu(2+)配位环境提出了各种建议模型。在这项研究中，我们使用了天然 Aβ肽的亲水截断部分来探测肽的 Cu(2+)配位位点，结合了光谱学和外源配体结合研究。我们的研究表明，Aβ(1-16)结合了 1 当量的 Cu(2+)，但在 pK(a)约为 8.1 时显示出两种物质之间的平衡。吸收和圆二色性光谱数据的配位场分析表明，两种组分均具有五配位几何结构。我们研究了叠氮化物和 8-羟基喹啉与 Cu-Aβ结合的影响，并证明了在生理 pH 值下，在正方形金字塔活性位点的赤道平面上存在来自水的配体和第二个可交换的配位到铜的配体。
