BRAIN METAL INTERACTIONS IN ALZHEIMER'S DISEASE

描述（来自申请人摘要）：Abeta是一种金属结合蛋白 锌、铜和铁的含量升高， 脑AD Abeta与这些金属的相互作用介导了 肽，但结合的氧化还原活性金属离子（铜和铁）产生 它们的还原和O2依赖性的、无细胞的H2 O2产生。h2 o2是 形成最多的是Abeta 1 -42> Abeta 1 -40>大鼠Abeta 1，这一排名顺序反映了 参与淀粉样蛋白病理的肽，以及各自的 每种肽的H2 O2介导的毒性。这些发现很重要，因为 在AD中的淀粉样沉积物中存在Cu、Fe和Zn的显著富集， 伴随着新皮层严重氧化应激的迹象，因为 转基因动物中的A β淀粉样蛋白沉积诱导类似的氧化 标记。我们还发现AD患者脑中的Abeta具有羰基 由于H2 O2介导的攻击而形成的加合物， 蛋白酶抗性我们还发现，虽然Zn沉淀Abeta， 也抑制铜还原，H2 O2的形成，和Abeta神经毒性，这表明 它在斑块中的富集可能代表了一种稳态防御。我们 假设菌斑可能由于以下原因而变得氧化惰性 浓缩Zn，并且实际上可能由于锌与 氧化的Abeta最近的数据表明， AD脑中斑块负荷与氧化标志物之间的负相关性。的 这种相互竞争的更新的总体目标是澄清复杂的关系 大脑铜，锌，铁水平，淀粉样蛋白形成和氧化损伤之间， 在人类死后和携带淀粉样蛋白的转基因动物脑组织中。我们 假设升高Cu和Fe增强了 Zn可以抑制A β介导的氧化，但其代价是 淀粉样蛋白使用电感耦合等离子体光谱法，我们将测量 在APP转基因动物的脑中富集Cu、Zn和Fe， 发育性淀粉样沉积的结果。我们将测试是否瞄准 金属与Abeta的相互作用与生物可利用的螯合化合物， 穿过血脑屏障抑制体内Abeta毒性和淀粉样蛋白形成， 潜在治疗策略的基础。最后，我们将穿越ZnT 3 用APP 2576敲除新皮质中缺乏囊泡锌的小鼠 淀粉样蛋白转基因，以确定是否这个池的大脑锌 有助于淀粉样蛋白的形成，如果这种敲除将减弱淀粉样蛋白 阵

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.