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 indicate that the observed phenomenon is receptor-mediated, and its presumably represents intra-oxonal 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. The phenomenon will also be studied at the ultrastructural level; 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 injection into the CSF; 2) the possible exposure of CBF neurons to pathologic agent 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
Clinical Investigator Award (CIA) (K08)
Project #
1K08NS001230-01
Application #
3084040
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1987-07-01
Project End
1992-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
1
Fiscal Year
1987
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
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