Department of Microbiology, The University of Georgia, 805 Biological Sciences Bldg, Athens, GA, 30602, USA.
Center for Metalloenzyme Studies, The University of Georgia, Athens, GA, 30602, USA.
Sci Rep. 2021 Mar 23;11(1):6622. doi: 10.1038/s41598-021-86060-1.
One of the hallmarks of the most common neurodegenerative disease, Alzheimer's disease (AD), is the extracellular deposition and aggregation of Amyloid Beta (Aβ)-peptides in the brain. Previous studies have shown that select metal ions, most specifically copper (Cu) and zinc (Zn) ions, have a synergistic effect on the aggregation of Aβ-peptides. In the present study, inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the metal content of a commercial recombinant human Aβ peptide. Cu and Zn were among the metals detected; unexpectedly, nickel (Ni) was one of the most abundant elements. Using a fluorescence-based assay, we found that Aβ peptide in vitro aggregation was enhanced by addition of Zn and Ni, and Ni-induced aggregation was facilitated by acidic conditions. Nickel binding to Aβ peptide was confirmed by isothermal titration calorimetry. Addition of the Ni-specific chelator dimethylglyoxime (DMG) inhibited Aβ aggregation in absence of added metal, as well as in presence of Cu and Ni, but not in presence of Zn. Finally, mass spectrometry analysis revealed that DMG can coordinate Cu or Ni, but not Fe, Se or Zn. Taken together, our results indicate that Ni ions enhance, whereas nickel chelation inhibits, Aβ peptide in vitro aggregation. Hence, DMG-mediated Ni-chelation constitutes a promising approach towards inhibiting or slowing down Aβ aggregation.
阿尔茨海默病（AD）是最常见的神经退行性疾病之一，其特征之一是大脑中淀粉样β（Aβ）肽的细胞外沉积和聚集。先前的研究表明，某些金属离子，特别是铜（Cu）和锌（Zn）离子，对 Aβ肽的聚集具有协同作用。在本研究中，我们使用电感耦合等离子体质谱法（ICP-MS）来确定商业重组人 Aβ肽的金属含量。检测到的金属包括 Cu 和 Zn；出人意料的是，Ni 是最丰富的元素之一。通过荧光测定法，我们发现 Zn 和 Ni 的添加可增强 Aβ肽的体外聚集，并且酸性条件可促进 Ni 诱导的聚集。通过等温热力学滴定法证实了 Ni 与 Aβ肽的结合。Ni 特异性螯合剂二甲基乙二肟（DMG）的添加可抑制无外加金属、外加 Cu 和 Ni 以及外加 Zn 时的 Aβ聚集。最后，质谱分析表明，DMG 可以与 Cu 或 Ni 配位，但不能与 Fe、Se 或 Zn 配位。综上所述，我们的结果表明，Ni 离子增强 Aβ肽的体外聚集，而镍螯合抑制 Aβ肽的聚集。因此，DMG 介导的 Ni 螯合可能是抑制或减缓 Aβ聚集的一种有前途的方法。
