METAL IONS AND PROTEIN STRUCTURE IN ALZHEIMER'S DISEASE

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。 阿尔茨海默病(AD)是一种神经退行性疾病，涉及一种自然发生的蛋白质--淀粉样β蛋白(Abeta)的错误折叠，最近发现它与铜和锌等金属离子的结合有关(Miller，2006)。金属动态平衡的紊乱被认为参与了错误折叠过程，导致氧化损伤和神经元退化。虽然这种疾病通常被认为是一种中枢神经系统(CNS)疾病，但越来越多的证据表明，在疾病过程中，非神经器官，如眼睛、胰腺、脾或肝脏，都受到了影响。这些发现提示AD可能是一种全身性疾病，这些组织的活检可能为早期诊断和治疗提供一种手段。然而，非神经元组织中的Abeta、微量金属和其他生化变化在疾病进展过程中的作用仍远未被了解。因此，这项计划的目标是研究阿尔茨海默病小鼠模型中受淀粉样蛋白影响的器官的组织，包括眼、肾、肝和脾。我们将使用同步辐射XRF微探针，在疾病的不同时间点，从临床前期到晚期，对组织中微量金属的成分和分布进行成像。这些结果将与我们在脑组织中的发现进行比较，并与常规组织学染色和同步辐射红外成像(AT NSLS)相关联，以了解受影响器官中金属分布/积累与有机生化变化之间的系统关系。

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. Alzheimer's disease (AD) is a neurodegenerative disorder that involves the misfolding of a naturally occurring protein, amyloid beta (Abeta), which has recently been associated with the binding of metal ions such as copper and zinc (Miller, 2006). Disturbance of metal homeostasis is believed to be involved in the misfolding process, leading to oxidative damage and the degeneration of neurons. Although this disease is generally considered a central nervous system (CNS) disorder, accumulating evidence suggested the involvement of non-neuronal organs, such as the eyes, pancreas, spleen or liver, during the course of the disease. These findings suggest that AD may be a systemic disease and perhaps biopsies of these tissues may provide a means for early diagnosis and treatment. However, the roles of Abeta, trace metals, and other biochemical changes in non-neuronal tissue during disease progression are still far from being understood. Therefore, the goal of this proposal is to study tissues from amyloid-affected organs including the eye, kidney, liver and spleen in a mouse model of AD. We will use using synchrotron XRF microprobe to image trace metal composition and distribution in the tissue at different time points during the disease, from pre-clinical stage to terminally diseased. These results will be compared with our findings from brain tissue and correlated with conventional histological staining and synchrotron infrared imaging (at NSLS), in order to understand the systemic relationship between metal distribution/accumulation and organic biochemical changes in the affected organs.