It has been demonstrated previously that fetal cholinergic basal forebrain grafts survive and improve memory function in a variety of animal models of Alzheimer's disease including lesioned rodents, aged rodents, and lesioned nonhuman primates. This suggests that fetal cholinergic grafting may be an innovative strategy for the treatment of the cholinergic deficit consistently observed in Alzheimer's disease. The present proposal aims to establish the structural and functional efficacy of fetal cholinergic grafting in aged monkeys, an essential step prior to initiating clinical trials of cholinergic grafting for the treatment of alzheimer's disease. In this regard, we have recently demonstrated that fetal nigral grafts survive in a patient with Parkinson's disease in a manner indistinguishable from that seen in animal models, indicating that data gathered in animal models have high predictive validity for grafting studies in humans. These findings increase our enthusiasm for the use of neural transplantation for the treatment of neurological diseases such as Alzheimer's disease. In the previous funding period, we demonstrated that fetal cholinergic allografts survive long-term following grafting into nonhuman primates. Further, we demonstrated that grafts of cells genetically modified to secrete human NGF can prevent the degeneration of cholinergic basal forebrain neurons in young adult and aged monkeys. Based upon these and other data, the present proposal aims to establish the optimal fetal donor tissue for transplantation and establish the structural and functional efficacy of fetal cholinergic grafts and fetal cholinergic/NGF cografts in aged monkeys. Xenografts extensively recircuit the damaged mammalian brain and have great clinical potential as a source of donor tissue for transplantation. In this regard, clinical trials employing porcine and bovine cells have recently been initialed for the treatment of Parkinson's disease and pain control, respectively. We will first attempt to identify an optimal source of fetal cells donor by comparing the ability of fetal cholinergic neurons derived from porcine, monkey, and human sources to survive and reinnervate the aged monkey hippocampus in aged nonhuman primates. All evidence gathered in animal models and human autopsy cases demonstrate that only 5-10 percent of grafted neurons survive transplantation. therefor, we will attempt to increase cholinergic cell survival and innervation by cografting fetal basal forebrain neurons with cells genetically modified to secrete human NGF. Lastly, we will determine whether fetal cholinergic grafts and/or fetal cholinergic/NGF cografts can ameliorate the cognitive decline observed in aged monkeys. These studies will determine the value of grafting of fetal cholinergic neurons as a treatment strategy for the cholinergic deficit in dementing illnesses such as Alzheimer's disease.
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