A salient feature of Alzheimer's and other age-associated neurodegenerative diseases is the selective vulnerability of particular neural pathways. Since the development and maintenance of neural connections is supported by neural trophic factors, trophic dysfunction represents one possible pathogenetic mechanism for such disorders. The long range research interests of the Principal Investigator are to understand the nature of neural trophic interactions and how they may be perturbed in human disease. In previous years of support from this grant, primary reaggregating cell cultures have been utilized and immortalized central nervous system neurons have been generated to study the trophic interactions that establish and maintain the septohippocampal pathway, which plays an essential role in cognitive function and is prominently affected in Alzheimer's Disease. The goals of the present renewal application are to: I) To utilize reaggregating cell cultures and primary neuronal monolayer cultures to further study the cellular and molecular mechanisms that regulate the expression and actions of nerve growth factor and its receptor in this system; II) To further characterize the cellular and molecular properties of immortal central neural cell lines generated from the septal region as a model system to study the neuronal response to trophic signals from the hippocampal region; and III) To further characterize the cellular and molecular properties of central neural cell lines generated from the hippocampal region. In particular, immunochemical and biochemical techniques will be employed to characterize a putative novel """"""""Neuronal Trophic Activity"""""""" expressed by one of the hippocampal-derived cell lines, HN10, which elevates the activity of choline acetyltransferase, the biosynthetic enzyme for acetylcholine, in primary septal monolayer cultures. The results of these studies will further exploit the utility of somatic cell fusion techniques for generation of clonal central nervous system cell lines, particularly from cell populations that are post- mitotic, as a strategy to investigate neural trophic mechanisms and for the identification of novel trophic substances. Such cell lines represent a potential source for isolation of such factors, and also a potential """"""""delivery system"""""""" via neural grafting techniques. The technology and information that is generated from these investigations will serve as a strategy to study trophic interactions in other brain circuits in future years and to investigate possible changes or dysfunctions that occur both in the aging brain and in age-associated brain diseases. (Note: Bold-face type indicates sections where significant revisions or new information was added).
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