THE DISTRIBUTION OF FE, CU AND ZN IN A ALZHEIMER?S DISEASE MICE MODEL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 人β-淀粉样前体蛋白(APP)转基因(TG)小鼠是一个公认的模型 治疗阿尔茨海默氏症。它被广泛用于病理学研究、诱变实验和 治疗药物的筛选。脑内高β淀粉样蛋白水平的APP TG小鼠显示 突触丢失、行为改变和突触传递缺陷。最近，参与了 阿尔茨海默病病理中的氧化还原活性金属已被确定。我们 假设转基因小鼠中APP的过度表达正在影响金属动态平衡， 因此，金属在大脑中的分布。微焦X射线荧光成像是最好的 人APP转基因小鼠海马铁、铜、锌分布的可视化技术 和健康(非转基因)对照。我们预计会检测到铜和锌浓度的增加 在斑块里。将尝试在斑块和健康组织上进行铜和铁的微量XANES监测 金属氧化状态的可能差异。在老鼠模型上的工作有很大的进展 与阿尔茨海默病患者脑组织死后分析相比具有优势。它允许 高度干扰，如监测不同时间点的疾病 进展，在给予不同的治疗剂期间或作为结果 特定的突变。在这项研究中，我们将分析两个不同年龄的小鼠的大脑： 斑块形成前后。拟议的研究将有助于揭示 金属离子在阿尔茨海默病发病中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human beta-amyloid precursor protein (APP) transgenic (Tg) mice is a well established model for Alzheimer's disease. It is widely used for pathology studies, mutagenesis experiments and screening of therapeutic agents. APP Tg mice with high beta-amyloid levels in the brain show synapse loss, behavioral changes, and synaptic transmission deficit. Recently, involvement of the redox active metals in the pathology of Alzheimer's disease has been identified. We hypothesize that overexpression of APP in Tg mice is affecting the metal homeostasis and, thus, the metal distributions in brain. Micro-focus X-ray fluorescent imaging is the best technique to visualize the Fe, Cu, Zn distributions in the hippocampus of human APP Tg mice and healthy (non transgenic) control. We expect to detect increased Cu and Zn concentrations in plaques. Cu and Fe micro-XANES will be attempted on plaques and healthy tissues to monitor possible differences in the metal oxidation states. Work on the mice model has enormous advantages compared to postmortem analysis of brain tissues of Alzheimer's patients. It allows a high degree of interference, such as monitoring at different points in time as the disease progresses, during administration of different therapeutic agents or as a consequence of specific mutations. In this proposal we will analyze brains of mice at two different ages: before and after plaques formation. The proposed study will help to uncover the involvement of metal ions in the onset of Alzheimer's disease.