Basal forebrain cholinergic neuronal degeneration is a prominent component of neuronal loss in AlzheimerUs disease (AD). In rats and primates, infusions of nerve growth factor (NGF) intracerebroventricularly (ICV) prevent injury-induced cholinergic neuronal degeneration. Gene therapy may allow the intraparenchymal delivery NGF to the CNS chronically to prevent the cholinergic neuronal degereration in AD. Our objective is to determine whether neurotrophic factor delivery by gene therapy can prevent long-term basal forebrain cholinergic neuronal degeneration in correlative primate models of AD. Retroviral vectors were used to genetically modify primary autologous primate fibroblasts to produce and secrete NGF or b-galactosidase (controls). These cells were grafted to the basal forebrain region of adult rhesus monkeys after fornix transections for periods of up to eight months to assess their ability to prevent injury-induced cholinergic neuronal degeneration (n=6 NGF recipients and 5 b-gal recipients). NGF-transduced cells secreted 13.210.7 (SEM) ng NGF/106 cells/hr in vitro; control cells produced no detectable NGF. After one month in vivo, NGF-secreting cells prevented the degeneration of 67.8 18.4% of cholinergic neurons as assessed by low-affinity neurotrophin receptor (p75) immunocytochemistry, whereas only 27.215.8% of neurons remained detectable among b-gal graft recipients (p,0.05). After 8 months, recipients of NGF-secreting grafts still showed a persistence of 70.4% of neurons. NGF ELISA of grafts after 8 months in vivo showed production of 24.4 ng NGF/gm tissue, whereas no NGF was detected in control grafts. No adverse morphological or functional effects of grafts on the host were detected. We conclude that NGF delivery by gene therapy can prevent cholinergic neuronal degeneration for extended periods in vivo and may be useful in treating the cholinergic component of neuronal loss in AD. *KEY*AlzheimerUs disease, Nerve growth factor, Neurotrophins, Aging, Primate, Rhesus monkey

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000169-35
Application #
5219969
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
35
Fiscal Year
1996
Total Cost
Indirect Cost
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Almodovar, Sharilyn; Swanson, Jessica; Giavedoni, Luis D et al. (2018) Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques. Viral Immunol 31:206-222
Ciupe, Stanca M; Miller, Christopher J; Forde, Jonathan E (2018) A Bistable Switch in Virus Dynamics Can Explain the Differences in Disease Outcome Following SIV Infections in Rhesus Macaques. Front Microbiol 9:1216
Comrie, Alison E; Gray, Daniel T; Smith, Anne C et al. (2018) Different macaque models of cognitive aging exhibit task-dependent behavioral disparities. Behav Brain Res 344:110-119
Day, George Q; Ng, Jillian; Oldt, Robert F et al. (2018) DNA-based Determination of Ancestry in Cynomolgus Macaques (Macaca fascicularis). J Am Assoc Lab Anim Sci 57:432-442
Carroll, Timothy D; Jegaskanda, Sinthujan; Matzinger, Shannon R et al. (2018) A Lipid/DNA Adjuvant-Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge. J Infect Dis 218:856-867
Feng, Jun-Feng; Liu, Jing; Zhang, Lei et al. (2017) Electrical Guidance of Human Stem Cells in the Rat Brain. Stem Cell Reports 9:177-189
Han, Pengcheng; Nielsen, Megan; Song, Melissa et al. (2017) The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques. Front Aging Neurosci 9:180
Pittet, Florent; Johnson, Crystal; Hinde, Katie (2017) Age at reproductive debut: Developmental predictors and consequences for lactation, infant mass, and subsequent reproduction in rhesus macaques (Macaca mulatta). Am J Phys Anthropol 164:457-476
Kyle, Colin T; Stokes, Jared; Bennett, Jeffrey et al. (2017) Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: Preservation of subfield volumes in aging. Hippocampus :

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