Neurotrophic factors can induce and maintain differentiation and prevent naturally occurring and experimentally induced neuronal cell death. Therefore, these peptides are especially attractive agents for the treatment of neurodegenerative diseases, such as Alzheimer's disease (AD). However, although much is known about the roles of neurotrophic factors in restoring cell phenotype following injury in the adult mammalian brain, the mechanisms whereby these peptides prevent neuronal cell death are less well understood. One difficulty in interpreting experiments designed to clarify this aspect of the biology of neurotrophic factors is the absence of definitive markers for dying neurons. The present proposal utilizes recently developed methods for labeling degenerating cells (the terminal transferase-mediated dUTP- biotin nick end labeling [TUNEL] staining method for nuclei and DNA laddering in Southern blots) to examine two well-characterized models of experimental degeneration of basal forebrain cholinergic and anterior thalamic neurons for evidence of neuronal death or programmed cell death. To assess the effects of neurotrophic factors in these models of neuronal cell deaths, we will damage the appropriate axon-specific paths (fimbria- fornix model and cingulatory model) and will examine NGF and CNTF respectively can reduce or eliminate TUNEL labeling or DNA laddering in dying neurons. In parallel studies, using tissues from individuals with AD or other neurodegenerative diseases, we will use TUNEL labeling and DNA laddering study the death of subsets of neurons, the existence of apoptic mechanisms and the progression of disease. Finally, in studies of axonal transport we will investigate further the mechanisms whereby signals are transduced by neurotrophins in the central nervous system. In concert, these studies will clarify critical issues relevant to neuronal cell death in the adult mammalian brain and the potential of neurotrophic factors as therapeutic agents to ameliorate death of neurons in human neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG010480-06
Application #
2334206
Study Section
Project Start
Project End
Budget Start
1995-10-01
Budget End
1996-09-30
Support Year
6
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Wong, Philip C; Cai, Huaibin; Borchelt, David R et al. (2002) Genetically engineered mouse models of neurodegenerative diseases. Nat Neurosci 5:633-9
Wong, P C; Cai, H; Borchelt, D R et al. (2001) Genetically engineered models relevant to neurodegenerative disorders: their value for understanding disease mechanisms and designing/testing experimental therapeutics. J Mol Neurosci 17:233-57
Qiao, X; Chen, L; Gao, H et al. (1998) Cerebellar brain-derived neurotrophic factor-TrkB defect associated with impairment of eyeblink conditioning in Stargazer mutant mice. J Neurosci 18:6990-9
Knusel, B; Gao, H; Okazaki, T et al. (1997) Ligand-induced down-regulation of Trk messenger RNA, protein and tyrosine phosphorylation in rat cortical neurons. Neuroscience 78:851-62
Hughes, P E; Alexi, T; Hefti, F et al. (1997) Axotomized septal cholinergic neurons rescued by nerve growth factor or neurotrophin-4/5 fail to express the inducible transcription factor c-Jun. Neuroscience 78:1037-49
Sukhov, R R; Cayouette, M H; Radeke, M J et al. (1997) Evidence that perihypoglossal neurons involved in vestibular-auditory and gaze control functions respond to nerve growth factor. J Comp Neurol 383:123-34
Koliatsos, V E; Price, D L (1996) Axotomy as an experimental model of neuronal injury and cell death. Brain Pathol 6:447-65
Qiao, X; Hughes, P E; Venero, J L et al. (1996) NT-4/5 protects against adrenalectomy-induced apoptosis of rat hippocampal granule cells. Neuroreport 7:682-6
Chan, K M; Lam, D T; Pong, K et al. (1996) Neurotrophin-4/5 treatment reduces infarct size in rats with middle cerebral artery occlusion. Neurochem Res 21:763-7
Qiao, X; Hefti, F; Knusel, B et al. (1996) Selective failure of brain-derived neurotrophic factor mRNA expression in the cerebellum of stargazer, a mutant mouse with ataxia. J Neurosci 16:640-8

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