FUNCTIONAL ANALYSIS OF ASTROCYTE DERIVED APOE3 AND APOE4

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DESCRIPTION: (Adapted from the application) The candidate (Anne Fagan Niven) received her Ph.D. in Neuroscience from the University of California, San Diego in 1992, and has a history of productive research investigating neuronal plasticity in the developing and injured nervous system. The candidate has expertise in cognitive neuroscience, neuronal development, neuroanatomy, and molecular neurobiology. Recent work at Washington University School of Medicine (WUSM) has fostered an interest in the etiology of neurodegenerative disease, in particular, the mechanism(s) by which apolipoprotein (ApoE) E4 is a risk factor for Alzheimer's disease (AD). Since ApoE is known to be an important regulator of plasma cholesterol metabolism, proper investigation of its role in AD, as well as in the normal brain, will require knowledge of: 1) AD, 2) cell biology, and 3) cholesterol/lipid metabolism, areas in which the candidate has little background. The proposed plan will provide the candidate with an additional period of mentored research in order to gain expertise in these three areas. The immediate career goal is to initiate a research program investigating the connection between ApoE4 and AD. Importantly, the scientific and technical expertise gained in the course of these studies will allow the candidate to attain her long-term goal; to establish an independent, multidisciplinary research career in neuroscience, with an emphasis on neuronal growth and repair as it relates to neurodegenerative disease. In the proposed study, it is hypothesized that brain-derived lipoproteins containing ApoE4 are inherently different in their composition/structure than those containing ApoE3, which in turn affects their ability to transport cholesterol/lipid, and/or affect AB metabolism. Utilizing transgenic mice which express human ApoE3 or ApoE4 by astrocytes, the candidate will characterize the composition/structure of astrocyte-derived lipoprotein particles and test their ability to transport cholesterol/lipid and affect AB metabolism in vitro and in vivo. David M. Holtzman, M.D (mentor) will provide training in AD, models of neurodegenerative disease, and cell biology; Alan L. Schwartz, M.D., Ph.D. (co-mentor), cell biology; and consultants, cell biology and lipid metabolism. WUSM, the Department of Neurology, and its associated Alzheimer's Disease Research Center has well-established research programs and a renowned group of faculty committed to research, education, and training. The many educational and technical resources available to the candidate at WUSM, in combination with the strong research programs of the mentor, co-mentor, and consultants, will provide the comprehensive training necessary to achieve her career goals.