We have recently demonstrated that neurons are primarily responsible for NGF mRNA expression in the normal adult rodent brain. Limbic seizure induction results in a dramatic increase in NGF mRNA levels within distinct populations of neurons capable of expression NGF. We have also found that glial cells are capable of high levels of GNF mRNA synthesis in culture. We are interested in determining how NGF is processed, secreted and transported to target neurons by these different cell types. The wide variety of CNS cell types capable of NGF synthesis and their different modes of regulation suggests that NGF production may be altered in conditions such as Alzheimer's disease which may affect its ability to provide critical support for cholinergic neurons which degenerate in this disease. In the proposed studies we will (1) evaluate the cellular sites of synthesis of NGF mRNA in control and Alzheimer's disease brains, (2) determine whether increase NGF mRNA synthesis in the rat hippocampal dentate granule cell layer results in the expression, proper processing and transport of the NGF protein to target neurons, (3) express recombinant human NGF and develop antibodies that efficiently recognize human NGF and its precursor, (4) examine the regional levels of NGF protein in control and Alzheimer's disease tissue, and (5) identify proteases responsible for processing and forming complexes with human NGF. These studies of the regulation of functional NGF expression will be important for developing and evaluating therapeutic strategies of increasing NGF levels within the brain.
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