Transplantation of embryonic dopamine (DA) neurons as an experimental therapy for Parkinson's disease (PD) is currently under evaluation. The non-human primate treated with the neurotoxin MPTP has served as an important animal model for the disease and the grafting paradigm, and has had significant predictive value for results of early clinical trials. Despite some encouraging clinical findings, relative survival of grafted DA neurons is low and improvement of behavioral symptoms is incomplete. Part of the disparity between results in animals and PD patients may relate to failure of animal studies to model certain characteristics of potential recipients of graft therapy that impact significantly on the environment of grafted cells. One characteristic of this patient population that can be examined in animals is the influence of chronological age of the transplant recipient. The interactions between age-related changes inherent to this system in graft recipients, the response of the aging system to accelerated loss of nigral DA neurons, and the impact these changes have on the environment for grafted tissue only recently have received attention. We have found that the viability and function of grafted DA neurons is profoundly diminished in DA-depleted aged rats. In addition, these aged animals exhibit important deficits in compensatory responses to DA depletion including decreased striatal neurotrophic activity. Recent clinical results also suggest diminished graft efficacy in elderly patients. Advancing chronological age of the transplant recipient may represent a previously under-appreciated risk of diminished graft viability and function that may mandate study of novel grafting strategies 1 to achieve good therapeutic results. It is the goal of this proposal to evaluate the influence of chronological age of the host on graft viability and function in MM?-treated non-human primates. Tissue from single donors will be divided for implantation into pairs of young adult and aged hemiparkinsonian monkeys, with behavioral, mophological, and biochemical techniques employed to study rates of apoptosis in grafts, survivai, neurite outgrowth and release of DA from grafted cells, and receptor, metabolic and -trophic responses in the host. Additional analyses will examine aging-related changes in microvasculature and oxidative stress in the graft environment. These studies will provide valuable information on the response of the aged brain to accelerated DA neuron loss, the interaction between aging in the host and graft viability, indicate mechanisms of intervention with graft survival and function in the aged brain, and will aid in matching patients with the optimal therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG017092-04S1
Application #
6751077
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Finkelstein, Judith A
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2003-06-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$106,220
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Kanaan, Nicholas M; Kordower, Jeffrey H; Collier, Timothy J (2010) Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys. Neurobiol Aging 31:937-52
Kanaan, Nicholas M; Kordower, Jeffrey H; Collier, Timothy J (2008) Age and region-specific responses of microglia, but not astrocytes, suggest a role in selective vulnerability of dopamine neurons after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure in monkeys. Glia 56:1199-214
Kanaan, N M; Kordower, J H; Collier, T J (2008) Age-related changes in dopamine transporters and accumulation of 3-nitrotyrosine in rhesus monkey midbrain dopamine neurons: relevance in selective neuronal vulnerability to degeneration. Eur J Neurosci 27:3205-15
Collier, Timothy J; Lipton, Jack; Daley, Brian F et al. (2007) Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: diminished compensatory mechanisms as a prelude to parkinsonism. Neurobiol Dis 26:56-65
Kanaan, Nicholas M; Kordower, Jeffrey H; Collier, Timothy J (2007) Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamine neurons: relevance to selective neuronal vulnerability. J Comp Neurol 502:683-700
Collier, Timothy J; Dung Ling, Zao; Carvey, Paul M et al. (2005) Striatal trophic factor activity in aging monkeys with unilateral MPTP-induced parkinsonism. Exp Neurol 191 Suppl 1:S60-7
Collier, Timothy J; Greene, James G; Felten, David L et al. (2004) Reduced cortical noradrenergic neurotransmission is associated with increased neophobia and impaired spatial memory in aged rats. Neurobiol Aging 25:209-21
Collier, Timothy J; Steece-Collier, Kathy; Kordower, Jeffrey H (2003) Primate models of Parkinson's disease. Exp Neurol 183:258-62
Pitzer, Mark R; Sortwell, Caryl E; Daley, Brian F et al. (2003) Angiogenic and neurotrophic effects of vascular endothelial growth factor (VEGF165): studies of grafted and cultured embryonic ventral mesencephalic cells. Exp Neurol 182:435-45
Collier, Timothy J; Sortwell, Caryl E; Elsworth, John D et al. (2002) Embryonic ventral mesencephalic grafts to the substantia nigra of MPTP-treated monkeys: feasibility relevant to multiple-target grafting as a therapy for Parkinson's disease. J Comp Neurol 442:320-30

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