BRAIN METAL INTERACTIONS IN ALZHEIMER'S DISEASE

描述(摘自申请者的摘要)：Abeta是一种金属结合蛋白 它与锌、铜和铁的高度一起堆积在 公元后的大脑。Abeta与这些金属的相互作用调节了 多肽，但氧化还原活性金属离子(铜和铁)的结合产生 它们的还原和依赖氧气的、无细胞的过氧化氢的产生。双氧水是 由Abeta1-42；Abeta1-40；Rate Abeta1；Abeta1-42；Abeta1-40；Rate Abeta组成最多，这种等级顺序反映了 多肽在淀粉样蛋白病理中的作用及其各自的 过氧化氢对各多肽的毒性作用。这些发现很重要，因为 阿尔茨海默病患者淀粉样蛋白沉积中铜、铁、锌的含量显著增加。 伴随着大脑皮层严重氧化应激的迹象，因为 转基因动物体内的Aβ淀粉样蛋白沉积可引起类似的氧化 记号笔。我们还发现阿尔茨海默病患者大脑中的Abeta具有羰基 作为过氧化氢介导的攻击的结果而形成的加合物，并可能诱导 蛋白水解酶抗性。我们还发现，虽然锌沉淀了Abeta，但它 也抑制铜还原、过氧化氢形成和Aβ神经毒性，提示 它在斑块中的丰富可能代表了一种动态平衡防御。我们 假设斑块可能成为氧化惰性的结果 富集锌，实际上可能是由于锌与 氧化了Abeta。这种可能性得到了最近数据的支持，这些数据表明 阿尔茨海默病患者脑内斑块负荷与氧化标记物呈负相关。这个 这一竞争性更新的总体目标是澄清复杂的关系 大脑铜、锌和铁水平、淀粉样蛋白形成和氧化损伤之间的关系， 在人类死后和含有淀粉样蛋白的转基因动物脑组织中。我们 假设铜和铁的升高加剧了由铅引起的氧化损伤 Abeta，但锌以形成为代价抑制Abeta介导的氧化 淀粉样蛋白。使用电感耦合等离子体光谱仪，我们将测量 APP转基因动物脑内铜、锌、铁的富集性 发育中淀粉样蛋白沉积的后果。我们将测试目标是否 金属与Abeta与一种生物可利用的螯合化合物的相互作用 交叉的BBB在体内抑制Abeta毒性和淀粉样蛋白的形成，因为 为潜在的治疗策略奠定了基础。最后，我们将穿越ZnT3 使用APP2576基因敲除小鼠的新皮质中缺少水泡状锌 携带淀粉样蛋白转基因来确定这一脑锌池 有助于淀粉样蛋白的形成，如果这种敲除会减弱淀粉样蛋白 队形。

DESCRIPTION (From the applicant's abstract): Abeta is a metal binding protein which accumulates together with elevations of zinc, copper and iron in the brain in AD. Abeta interactions with these metals mediate the precipitation of the peptide, but binding of the redox active metal ions (Cu and Fe) engenders their reduction and the O2-dependent, cell-free generation of H2O2. H2O2 is formed most by Abeta1-42> Abeta1-40>rat Abeta, a rank order that mirrors involvement of the peptides in amyloid pathology, and also the respective H2O2-mediated toxicity of each peptide. These findings are important because there is a striking enrichment of Cu, Fe, and Zn in amyloid deposits in AD, accompanied by signs of severe oxidation stress in the neocortex, and because Abeta amyloid deposition in transgenic animals induces similar oxidation markers. We have also found that Abeta in the brain in AD bears carbonyl adducts which form as consequence of H2O2-mediated attack and may induce protease resistance. We have also found that although Zn precipitates Abeta, it also inhibits Cu reduction, H2O2 formation, and Abeta neurotoxicity, suggesting that its enrichment in plaque may represent a homeostatic defense. We hypothesize that plaque may become oxidatively inert as a consequence of concentrating Zn, and indeed may form because of the interaction of zinc with oxidized Abeta. This possibility is supported by recent data indicating an inverse correlation between plaque load and oxidation markers in AD brain. The overall goal of this competing renewal is to clarify the complex relationship between cerebral Cu, Zn, and Fe levels, amyloid formation and oxidative damage, in human post-mortem and amyloid-bearing transgenic animal brain tissue. We hypothesize that elevated Cu and Fe potentiate the oxidation damage caused by Abeta, but that Zn quenches Abeta-mediated oxidation at the expense of forming amyloid. Using inductively coupled plasma spectrometry, we will measure the enrichment of Cu, Zn, and Fe in the brains of APP transgenic animals as a consequence of developmental amyloid deposition. We will test whether targeting the metal interaction with Abeta with a bioavailable chelating compound that crosses the BBB inhibits Abeta toxicity and amyloid formation in vivo, as the basis for a potential therapeutic strategy. Finally, we will cross the ZnT3 knockout mouse that lacks vesicular zince in its neocortex with the APP2576 amyloid-bearing transgenic to determine whether this pool of brain zinc contributes to amyloid formation and if this knockout will attenuate amyloid formation.