The mechanisms of neurodegeneration in Alzheimer disease (AD) are not well understood. Indentifying the extracellular signals that initiate neurodegeneration and the intracellular signals that promote this process, as well as understanding the regulation of these signals, may provide novel targets for the development of new preventive and therapeutic agents for AD. Some products of inflammatory reactions are neurotoxic. We have shown that prostaglandin's (PG) Ei and A about, major products of inflammatory reactions, are neurotoxic to adenosine 3',5' cyclic monophosphate (cA about MP)-induced differentiated neuroblastoma (NB) cells in culture and to a primary culture of embryonic rat hippocampal neurons. This degeneration is preceded by an increase in-A,B and ubiquitin levels; however, it is not known whether elevated levels of these proteins result in their enhanced secretion. It is also not known how Ap and ubiquitin interact, if at all, to cause degeneration in nerve cells. The involvement of intracellular signals other than Ap, ubiquitin and tau proteins has also not been adequately investigated. To study these issues, we propose the following specific aims: (1) to measure intracellular levels of APP mRNA, APP holoprotein, Ap peptide, ubiquitin mRNA, ubiquitin, as well as extracellular levels of APP, Ap and ubiquitin in differentiated NB cells after treatment with PGA,; (2) to determine whether PGA about-induced degeneration in differentiated NB cells leads to increased accumulation of ubiquitin-conjugated proteins, and to increased binding of A,B to the proteasome complex, (3) to investigate whether reduced expression of APP in NB cells provides protection, and whether reduced expression of ubiquitin and proteasome accelerates the rate of PGA about-mediated neurodegeneration in differentiated NB cells; (4) to identify early and late genes whose expression is altered during PGA'-induced degeneration of differentiated NB cells; and 5) to investigate whether PGA about-mediated degeneration of differentiated NB cells involves increased oxidative stress due either to reduced antioxidant enzyme activity or to increased production of reactive oxygen species (ROS).

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Special Emphasis Panel (ZRG1-BDCN-1 (04))
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Snyder, Stephen D
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University of Colorado Denver
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