METAL IONS AND PROTEIN STRUCTURE IN ALZHEIMER'S DISEASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 阿尔茨海默病（AD）是一种神经退行性疾病，涉及天然存在的蛋白质β淀粉样蛋白（Abeta）的错误折叠，最近发现其与金属离子（如铜和锌）的结合有关（米勒，2006）。金属稳态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变性。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，非神经元器官（如眼睛、胰腺、脾脏或肝脏）也会受累。这些发现表明，AD可能是一种全身性疾病，这些组织的活检可能提供了一种早期诊断和治疗的手段。然而，Abeta，微量金属和其他生化变化在疾病进展过程中在非神经元组织中的作用仍远未被理解。因此，本提案的目标是在AD小鼠模型中研究来自淀粉样蛋白影响的器官的组织，包括眼睛、肾脏、肝脏和脾脏。我们将使用同步辐射X射线荧光显微探针成像微量金属成分和分布在组织中的不同时间点的疾病，从临床前阶段到终末期疾病。这些结果将与我们从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（在NSLS）相关，以了解金属分布/积累和受影响器官的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.