Department of Chemistry and Biochemistry, University of Mississippi, 305 Coulter Hall, University, MS, 38677, USA.
Chembiochem. 2018 Nov 16;19(22):2360-2371. doi: 10.1002/cbic.201800446. Epub 2018 Oct 23.
Transition-metal-catalyzed oxidative stress is a widespread concern in the pathogenesis of Alzheimer's disease. However, the exact role of amyloid beta oligomers towards oxidative stress is widely debated. Assessing the oxidative nature of the oligomers in vitro is complicated by the different experimental conditions under which they are prepared. We have investigated Cu -catalyzed reactive oxygen species (ROS) generation by using oligomers prepared in phosphate-buffered saline (Aβ ) and in cell culture medium (Aβ ), and compared their activities with respect to the monomers and fibrils prepared at neutral and acidic pH. Although both are deca- to dodecamers, the Aβ oligomers have a spherical morphology and are smaller than the Aβ . The Aβ behaved as pro-oxidants; in contrast, Aβ quench OH generation attributed to CCM itself. Although the pro-oxidant oligomers showed oxidation, they also partially protect themselves from radical damage and maintain their overall spherical arrangement. The monomers and fibrils manifested antioxidant properties: radical scavenging as opposed to redox silencing. A dual role of Aβ species depending on the stage of the disease is proposed. In the earlier stages, the monomers can act as antioxidants, whereas at the later stages, the oligomers take on a pro-oxidant role. Kaempferol, a natural flavonoid, bound Cu in 2:1 ratio and abolished ROS production in all Aβ species. It also distinctly modified the folding landscape of Aβ species into new or altered morphologies.
过渡金属催化的氧化应激是阿尔茨海默病发病机制中的一个普遍关注点。然而，淀粉样β 寡聚体对氧化应激的确切作用仍存在广泛争议。评估寡聚体在体外的氧化性质很复杂，因为它们是在不同的实验条件下制备的。我们研究了使用在磷酸盐缓冲盐溶液（Aβ）和细胞培养基（Aβ）中制备的寡聚体中的 Cu 催化的活性氧物种（ROS）生成，并将它们的活性与在中性和酸性 pH 下制备的单体和纤维进行了比较。尽管两者都是十到十二聚体，但 Aβ 寡聚体具有球形形态且小于 Aβ。Aβ 表现为促氧化剂；相比之下，Aβ 猝灭了归因于 CCM 本身的 OH 生成。虽然促氧化剂寡聚体表现出氧化作用，但它们也部分保护自己免受自由基损伤并保持其整体球形排列。单体和纤维表现出抗氧化特性：与氧化还原沉默相反，清除自由基。提出了 Aβ 物种根据疾病阶段的双重作用。在早期阶段，单体可以作为抗氧化剂，而在晚期阶段，寡聚体则起促氧化剂的作用。山奈酚是一种天然类黄酮，以 2:1 的比例与 Cu 结合，并消除了所有 Aβ 物种中的 ROS 生成。它还明显地将 Aβ 物种的折叠景观改变为新的或改变的形态。
