Transplantation of fetal cholinergic basal forebrain (CBF) neurons has been successful in restoring cholinergic tone within CBF target regions and reversing cognitive dysfunction in aged and CBF lesioned rats. Although clinical trials employing grafts of fetal dopaminergic neurons are underway for the treatment of Parkinson's disease, trials using embryonic CBF grafts to treat cognitive dysfunction associated with damage to the basal forebrain cell groups seen in Alzheimer's disease (AD) requires further scientific investigation. Therefore, it is imperative to systematically study the structural and functional efficacy of CBF transplants in nonhuman primates. During the previous funding period we established that fetal basal forebrain neurons can survive implantation in nucleus basalis lesioned monkeys. However, graft size is relatively small compared to allografts of CBF neurons in rodents. The present continuation requests funds to study two approaches aimed at increasing graft size and maximizing host innervation in monkeys. The fun approach will compare the survival and host innervation of fetal CBF implants in immunosuppressed and immunocompetent basal forebrain-lesioned monkey hosts. These findings will provide crucial information concerning the need for immunosuppression in primates following neural grafting. The second approach involves cografting CBF neurons with a biological source of growth factors including nerve growth factor. In the previous funding period, we demonstrated the sensitivity of primate CBF neurons to the trophic and neurite promoting effects of grafted NGF-producing peripheral nerve. Thus the ability of transected peripheral nerve to enhance graft viability will be assessed in both untreated and immunosuppressed CBF lesioned monkeys. Since AD is a disease of the elderly, aged monkeys will be used as a second model of human geriatric memory dysfunction. The ability of fetal CBF grafts and peripheral nerve/CBF cografts to survive and innervate basal forebrain target zones in aged nonhuman primates will be determined. Finally, we will investigate the ability of CBF grafts and peripheral nerve/CBF cografts to reverse the cognitive dysfunction seen in aged monkeys. The data generated from this grant application will provide greater insight into the feasibility of the using a CBF transplantation strategy for the treatment of the cholinergic deficit in AD.
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