Recent work has shown that administration of nerve growth factor (NGF), a neurotrophin which is critical for the survival and phenotypic maintenance of cholinergic neurons, improves cognitive performance in aged rats. The goal of the work presented in this proposal is to explore basic neurobiological mechanisms responsible for NGF-induced enhancement of cognition in aged subjects. The guiding hypotheses are that NGF acts to normalize long-term synaptic plasticity mechanisms and protein kinase C activity. In addition, a novel method for delivering peripherally administered NGF to the brain will be characterized. Young (4 month old) and aged (22 month old) male Fischer 344 rats will be evaluated in behavioral tasks which preferentially involve the hippocampus, frontal cortex, or basal forebrain cholinergic system. Hippocampal synaptic plasticity will be measured to correlate with cognitive status. After baseline evaluation, the animal will receive either NGF or appropriate control solution. Peripherally administered NGF is conjugated to a transferrin receptor antibody to allow the transport of biologically active NGF into the brain. After four weeks of treatment, the rats will be re-evaluated in the behavioral and electrophysiological tests, then sacrificed to assess the activity of protein kinase C (PKC), an enzyme which has been shown to be involved in the regulation of both learning and brain plasticity, in the hippocampus, frontal cortex and septal area. Additional experiments will be performed to directly evaluate the relationship between NGF, PKC, hippocampal plasticity and spatial learning. Taken together, this work will provide important information concerning the extent and degree of age-related learning impairments, as well as potential electrophysiological and biochemical substrates for these problems. In addition, the work will determine the extent to which age-related cognitive problems can be reduced with NGF treatment, and provide insight into the mechanism(s) by which NGF is able to achieve its effects. Finally, this work will evaluate the efficacy of a novel means of delivering NGF to the brain which has clear advantages over conventional techniques in terms of potential clinical application.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010755-07
Application #
6055378
Study Section
Neurology A Study Section (NEUA)
Project Start
1991-09-29
Project End
2000-07-31
Budget Start
1999-09-01
Budget End
2000-07-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bimonte-Nelson, Heather A; Granholm, Ann-Charlotte E; Nelson, Matthew E et al. (2008) Patterns of neurotrophin protein levels in male and female Fischer 344 rats from adulthood to senescence: how young is ""young"" and how old is ""old""? Exp Aging Res 34:13-26
Granholm, Ann-Charlotte; Boger, Heather; Emborg, Marina E (2008) Mood, memory and movement: an age-related neurodegenerative complex? Curr Aging Sci 1:133-9
Paredes, D; Granholm, A-Ch; Bickford, P C (2007) Effects of NGF and BDNF on baseline glutamate and dopamine release in the hippocampal formation of the adult rat. Brain Res 1141:56-64
Williams, Brice; Granholm, Ann-Charlotte; Sambamurti, Kumar (2007) Age-dependent loss of NGF signaling in the rat basal forebrain is due to disrupted MAPK activation. Neurosci Lett 413:110-4
French, K L; Bimonte-Nelson, H A; Granholm, A C (2007) Galantamine effects on memory, spatial cue utilization, and neurotrophic factors in aged female rats. Cell Transplant 16:197-205
Williams, Brice J; Bimonte-Nelson, Heather A; Granholm-Bentley, Ann-Charlotte (2006) ERK-mediated NGF signaling in the rat septo-hippocampal pathway diminishes with age. Psychopharmacology (Berl) 188:605-18
Williams, Brice J; Eriksdotter-Jonhagen, Maria; Granholm, Ann-Charlotte (2006) Nerve growth factor in treatment and pathogenesis of Alzheimer's disease. Prog Neurobiol 80:114-28
French, Kristen L; Granholm, Ann-Charlotte E; Moore, Alfred B et al. (2006) Chronic nicotine improves working and reference memory performance and reduces hippocampal NGF in aged female rats. Behav Brain Res 169:256-62
Williams, Brice; Nelson, Matthew; Granholm, Ann-Charlotte et al. (2005) Altered NGF response but not release in the aged septo-hippocampal cholinergic system. Exp Neurol 196:30-40
Albeck, Dave; Mesches, Michael H; Juthberg, Sonya et al. (2003) Exogenous NGF restores endogenous NGF distribution in the brain of the cognitively impaired aged rat. Brain Res 967:306-10

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