Cuajungco M P, Goldstein L E, Nunomura A, Smith M A, Lim J T, Atwood C S, Huang X, Farrag Y W, Perry G, Bush A I
Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
J Biol Chem. 2000 Jun 30;275(26):19439-42. doi: 10.1074/jbc.C000165200.
Abeta binds Zn(2+), Cu(2+), and Fe(3+) in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn(2+) precipitates Abeta in vitro, and Cu(2+) interaction with Abeta promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H(2)O(2) (Abeta1-42 > Abeta1-40 > ratAbeta1-40). Because Zn(2+) is redox-inert, we studied the possibility that it may play an inhibitory role in H(2)O(2)-mediated Abeta toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu(2+), Zn(2+) rescued primary cortical and human embryonic kidney 293 cells that were exposed to Abeta1-42, correlating with the effect of Zn(2+) in suppressing Cu(2+)-dependent H(2)O(2) formation from Abeta1-42. Since plaques contain exceptionally high concentrations of Zn(2+), we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn(2+) in AD, where plaques form as the result of a more robust Zn(2+) antioxidant response to the underlying oxidative attack.
β淀粉样蛋白（Aβ）在体外能结合锌离子（Zn²⁺）、铜离子（Cu²⁺）和铁离子（Fe³⁺），在阿尔茨海默病（AD）患者的新皮质中，这些金属离子水平显著升高，且在淀粉样斑块沉积中尤其富集。Zn²⁺在体外能使Aβ沉淀，Cu²⁺与Aβ的相互作用会促进其神经毒性，这与金属还原以及无细胞状态下过氧化氢（H₂O₂）的生成相关（Aβ1-42 > Aβ1-40 > 大鼠Aβ1-40）。由于Zn²⁺是氧化还原惰性的，我们研究了它可能在H₂O₂介导的Aβ毒性中发挥抑制作用的可能性。与Cu²⁺共同孵育所导致的细胞毒性增强作用相反，Zn²⁺挽救了暴露于Aβ1-42的原代皮质细胞和人胚肾293细胞，这与Zn²⁺抑制由Aβ1-42生成Cu²⁺依赖性H₂O₂的作用相关。由于斑块中含有极高浓度的Zn²⁺，我们检测了AD受累组织中的氧化（8-羟基鸟苷）水平与组织学淀粉样蛋白负荷之间的关系，发现存在显著的负相关。这些数据表明Zn²⁺在AD中具有保护作用，在AD中，斑块的形成是对潜在氧化攻击的更强有力的Zn²⁺抗氧化反应的结果。
