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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS025655-05A1
Application #
3410983
Study Section
Neurology A Study Section (NEUA)
Project Start
1989-02-01
Project End
1996-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Emborg, M E; Ma, S Y; Mufson, E J et al. (1998) Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J Comp Neurol 401:253-65
Kordower, J H; Mufson, E J; Fox, N et al. (1997) Cellular delivery of NGF does not alter the expression of beta-amyloid immunoreactivity in young or aged nonhuman primates. Exp Neurol 145:586-91
Kordower, J H; Chen, E Y; Mufson, E J et al. (1996) Intrastriatal implants of polymer encapsulated cells genetically modified to secrete human nerve growth factor: trophic effects upon cholinergic and noncholinergic striatal neurons. Neuroscience 72:63-77
Emerich, D F; Winn, S R; Harper, J et al. (1994) Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. J Comp Neurol 349:148-64
Burke, M A; Mobley, W C; Cho, J et al. (1994) Loss of developing cholinergic basal forebrain neurons following excitotoxic lesions of the hippocampus: rescue by neurotrophins. Exp Neurol 130:178-95
Kordower, J H; Chen, E Y; Sladek Jr, J R et al. (1994) trk-immunoreactivity in the monkey central nervous system: forebrain. J Comp Neurol 349:20-35
Mufson, E J; Higgins, G A; Kordower, J H (1991) Nerve growth factor receptor immunoreactivity in the new world monkey (Cebus apella) and human cerebellum. J Comp Neurol 308:555-75
Mufson, E J; Presley, L N; Kordower, J H (1991) Nerve growth factor receptor immunoreactivity within the nucleus basalis (Ch4) in Parkinson's disease: reduced cell numbers and co-localization with cholinergic neurons. Brain Res 539:19-30
Hansen, J T; Fiandaca, M S; Kordower, J H et al. (1990) Striatal adrenal medulla/sural nerve cografts in hemiparkinsonian monkeys. Prog Brain Res 82:573-80
Kordower, J H; Fiandaca, M S (1990) Response of the monkey cholinergic septohippocampal system to fornix transection: a histochemical and cytochemical analysis. J Comp Neurol 298:443-57

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