Atwood Craig S, Obrenovich Mark E, Liu Tianbing, Chan Hsien, Perry George, Smith Mark A, Martins Ralph N
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Brain Res Brain Res Rev. 2003 Sep;43(1):1-16. doi: 10.1016/s0165-0173(03)00174-7.
Although much maligned, the amyloid-beta (Abeta) protein has been shown to possess a number of trophic properties that emanate from the protein's ability to bind Cu, Fe and Zn. Abeta belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Abeta's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Abeta would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer's disease (AD). Given that oxidative stress promotes Abeta generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Abeta, and while evidence for direct Abeta neurotoxicity in vivo is scarce, we postulate that the product of Abeta's antioxidant activity, hydrogen peroxide (H(2)O(2)), is likely to mediate toxicity as the levels of this oxidant rise with the accumulation of Abeta in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H(2)O(2) and/or Abeta generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant activity of Abeta, we suggest that the excessive removal of Abeta may prevent adequate chelation of metal ions and removal of O(2)(-z.ccirf;), leading to enhanced, rather than reduced, neuronal oxidative stress.
尽管备受诋毁，但β-淀粉样蛋白（Aβ）已被证明具有多种营养特性，这些特性源于该蛋白结合铜、铁和锌的能力。Aβ属于一类能够捕获氧化还原金属离子的蛋白质（即使在轻度酸中毒条件下），从而防止它们与其他配体参与氧化还原循环。铜的配位似乎对Aβ自身的抗氧化活性至关重要，这一点已在体外以及大脑、脑脊液和血浆中得到证实。因此，可以预测Aβ对铜的螯合作用会减轻急性脑外伤和阿尔茨海默病（AD）所伴随的轻度酸中毒和氧化环境中的氧化应激。鉴于氧化应激会促进Aβ的生成，弥漫性淀粉样斑块的形成很可能是一种清除活性氧的代偿性反应。这篇综述权衡了支持Aβ营养特性和毒性特性的证据，虽然体内直接的Aβ神经毒性证据稀少，但我们推测Aβ抗氧化活性的产物过氧化氢（H₂O₂）可能会随着这种氧化剂在AD大脑中随着Aβ的积累而升高，从而介导毒性作用。我们提出，针对减少H₂O₂和/或Aβ生成的金属离子螯合剂、抗氧化剂、抗炎药和降低淀粉样蛋白的药物可能在降低神经毒性方面有效。然而，鉴于Aβ的抗氧化活性，我们认为过度清除Aβ可能会阻止金属离子的充分螯合和超氧阴离子（O₂⁻）的清除，导致神经元氧化应激增强而非减轻。
