METAL IONS AND PROTEIN STRUCTURE IN ALZHEIMER'S DISEASE

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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.