In the last decade, cognitive deficits displayed by rodents in animal models of Alzheimer's disease have been ameliorated following the neural grafting of fetal cholinergic cells and differentiated neuroblastoma cells. These data have led to the suggestion that neural implants may be a useful procedure for the treatment of neurodegenerative diseases such as Alzheimer's disease. However, a data base for such clinical trials has not been establish in non-human primates. A major obstacle in gathering such a data base is the lack of an adequate non-human primate model of cognitive dysfunction. The first goal of this proposal is to establish such a model. Neurotoxic lesions will be made in the nucleus basalis of Meynert of young and aged Cebus apella monkeys. This brain sites provides the major cholinergic input to the amygdala and neocortex and degenerate in certain diseases of cognitive dysfunction including Alzheimer's disease. Aged monkeys display cognitive dysfunction including Alzheimer's disease. Aged monkeys display cognitive deficits that are moderated by cholinomimetics suggesting that the memory impairments they display are partly mediated through cholinergic mechanisms. Creating lesions in aged monkeys may induce more robust cognitive deficits from which the effects of neural implants can better be evaluated. For clinical trials, the source of donor cells is a critical issue. Most experimental studies employ fetal primordia as donor material. Our research group has extensively investigated the potential of non-fetal differentiated neuroblastoma cells to serve as donor material. This proposal will directly compare the ability of differentiated neuroblastoma cells and fetal cholinergic primordia to survive transplantation into telencephalic brain sites and innervate the primate brain whose hose cholinergic system(s) have been impaired through neurotoxic lesions of the nucleus basalis of Meynert or the aging process. The final goal of this proposal is to determine whether grafts of cholinergic cells can ameliorate lesion-induced or age-related cognitive dysfunction in the non-human primate. These studies will be a major step determining the potential of neural implants to serve as an innovative therapeutic strategy for the treatment of neurodrogenerative diseases such as Alzheimer's disease. It will determine the ability of the age primate to serve as host for neural implants and will also create a non-human primate model of Alzheimer's disease for which other innovative strategies can be evaluated.
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