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.
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