Glutamic acid is the major excitatory amino acid in the brain, yet there is increasing evidence that its overabundance or ectopic expression leads to cell death in cases of cute insult and perhaps in progressive degeneration diseases such as Huntington's and Alzheimer's. Similarly, amyloid beta protein (ABP) is an apparently ubiquitous protein whose dense concentration in Alzheimer's plaques may lead to the death of the surrounding neurons. Glutamate excitotoxity and ABP toxicity are clearly involved in some of the major pathological conditions associated with the CNS, yet there are few drugs or reagents which are able to block or inhibit the two forms of cytotoxicity. It is the overall goal of this project to use newly developed cell culture assays to identify new molecules which inhibit or modulate the toxic effects of L-glutamate and ABP on nerve cells. This will be done by using these assays to identify and sequence protective molecules which may be made by CNS nerve and glial cells themselves and by examining the protective effects of identified growth factors. In addition, we will, in collaboration with Drs. Gage and Zivin, study a newly isolated neurotrophic growth factor which also protects cells from glutamate toxicity (Schwannoma derived growth factor, SDGF) in in vivo models to examine its potential protective effects in ischemia and its neurotrophic properties when over- expressed in CNS tissue grafts. These experiments should further our knowledge about the role of growth factors in neurodegenerative diseases and hopefully lead to the isolation of new molecules of therapeutic value.
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