This study will explore the surprising observation that, when injected into the lateral ventricle of the rat, both nerve growth factor (NGF) and a monoclonal antibody directed against the NGF receptor, IgG 192, are transported bilaterally to numerous neurons with topographic and morphologic characteristics of the cholinergic basal forebrain (CBF) system. The data indicated that the observed phenomenon is receptor-mediated, and it presumably represents intra-axonal retrograde transport. The present proposal has 3 major specific aims: 1) Thorough characterization of this phenomenon using radiolabeled NGF and IgG 192 in autoradiographic experiments and native IgG 192 in standard immunohistochemical experiments. Data will be obtained regarding the time course and relative efficiency of the accumulation of NGF and IgG 192 in neurons, in terminal fields and potentially at the portal of entry into neuropil. Choline acetyltransferase (CAT) immunohistochemistry will be used to confirm the putative cholinergic nature of the labeled neurons and to map the population of CBF neurons involved in the transport process; 2) other peptides and immunoglobulins will be radiolabeled and their ability to undergo similar transport will be assessed; 3) an already synthesized specific hybrid toxin, IgG 192 coupled to the A subunit of ricin toxin, will be injected into the rat lateral ventricle and its ability to produce a cholinergic deficit will be evaluated by morphologic and biochemical means. The CBF is one of the primary sites of neuronal degeneration in Alzheimer's disease (AD), and NGF has been shown to greatly decrease the cell death observed in CBF neurons following axotomy. If funded, this proposal will explore the extent to which NGF or other ligands that recognize the NGF receptor can be injected into cerebrospinal fluid (CSF) and reach the CBF in a specific manner. This will have important implications with regard to: 1) the potential administration of NGF or other drugs to a population of neurons of critical importance in AD by the relatively simple means of injections into the CSF; 2) the possible exposure of CBF neurons to pathologic agents that gain access to CSF, and; 3) the creation of an animal model of forebrain cholinergic deficit using a specific toxin that offers potentially superior specificity when compared to more classical lesioning techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025122-03
Application #
3410271
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Herron, P; Li, Z; Schweitzer, J B (1998) Effects of cholinergic depletion on evoked activity in the cortex of young and aged rats. Int J Dev Neurosci 16:633-43
Baskerville, K A; Schweitzer, J B; Herron, P (1997) Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat. Neuroscience 80:1159-69
Book, A A; Wiley, R G; Schweitzer, J B (1995) 192 IgG-saporin. 2. Neuropathology in the rat brain. Acta Neuropathol (Berl) 89:519-26
Singh, V; Schweitzer, J B (1995) Loss of p75 nerve growth factor receptor mRNA containing neurons in rat forebrain after intraventricular IgG 192-saporin administration. Neurosci Lett 194:117-20
Pallera, A M; Schweitzer, J B; Book, A A et al. (1994) 192 IgG-saporin causes a major loss of synaptic content in rat olfactory bulb. Exp Neurol 127:265-77
Book, A A; Wiley, R G; Schweitzer, J B (1994) 192 IgG-saporin: I. Specific lethality for cholinergic neurons in the basal forebrain of the rat. J Neuropathol Exp Neurol 53:95-102
Book, A A; Wiley, R G; Schweitzer, J B (1992) Specificity of 192 IgG-saporin for NGF receptor-positive cholinergic basal forebrain neurons in the rat. Brain Res 590:350-5
Thomas, L B; Book, A A; Schweitzer, J B (1991) Immunohistochemical detection of a monoclonal antibody directed against the NGF receptor in basal forebrain neurons following intraventricular injection. J Neurosci Methods 37:37-45
Ferguson, I A; Schweitzer, J B; Bartlett, P F et al. (1991) Receptor-mediated retrograde transport in CNS neurons after intraventricular administration of NGF and growth factors. J Comp Neurol 313:680-92
Ferguson, I A; Schweitzer, J B; Johnson Jr, E M (1990) Basic fibroblast growth factor: receptor-mediated internalization, metabolism, and anterograde axonal transport in retinal ganglion cells. J Neurosci 10:2176-89

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