This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Alzheimer's disease is a uniquely human disorder of old age that slowly destroys brain function. Recent research has shown that the disease is associated with a buildup of specific proteins in the brain; one of these proteins is amyloid- (A ), a fragment of the amyloid-precursor protein (APP) that forms senile plaques, and the other is the protein tau, which accumulates excessively in nerve cells. Transgenic mouse models have been created to study these proteins, but no mouse model fully resembles human Alzheimer's disease. For example, A -immunization therapy is remarkably successful in reducing A and improving behavior in mice, but in humans with Alzheimer's disease, the same treatment resulted in brain inflammation and shrinkage that were not evident in mouse models. These serious side-effects have impeded the application of this promising treatment to humans. In this innovative project, we use rhesus monkeys, which are biologically closer to humans than rodents, to establish better models for studying the basic mechanisms of Alzheimer's disease, and for testing new diagnostic and therapeutic methods. We will use two distinct and cutting edge approaches to express human mutant genes that cause Alzheimer's disease in rhesus monkeys; one expressing the genes locally in vulnerable regions of adult brain, and the other expressing the genes throughout the bodies of transgenic animals. We predict that these nonhuman primates will more faithfully recapitulate Alzheimer's disease than existing animal models. We will use state-of-the art imaging and sophisticated behavioral tests to determine how the Alzheimer genes affect the structure and function of the brain in living organisms. An AD monkey has been generated and a longitudinal study is ongoing, which include noninvasive imaging, cognitive behavioral evaluation and molecular characterization. Additionally, two additional pregnancies were confirmed.
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