Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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With the increased life expectancy in the western world today, the incidence of age-related neurodegenerative disease has also increased dramatically. Neurotransmission within the forebrain cholinergic system is impaired in senescence, and this system is also one of the primary targets in Alzheimer's Disease (AD). One prominent theory for this cholinergic degeneration suggests an impairment in the delivery of nerve growth factor (NGF) from hippocampal neurons to the basal forebrain septal cholinergic neurons. This process consists of a series of steps which must all function properly to efficiently deliver NGF. These steps include: synthesis and release of NGF by hippocampal neurons; binding to NGF receptors on septal cholinergic neurons; the bound receptors must trigger the appropriate second messenger systems; and retrograde transport of the NGF/NGF receptor complex to the septal neuron soma where it can optimally affect transcription. It is not know if NGF release from hippocampal neurons changes with aging, not is it known if NGF mediated responses within septal neurons change with age. These two questions will be investigated in the proposed experiments. Synthesis of NGF does not appear to be impaired, since NGF mRNA and protein levels are not depleted in the hippocampus of aged rats or patients with AD. However, expression of the high affinity NGF receptor (trkA) is decreased in aged rats and or patients with AD. However, expression of the high affinity NGF receptor (trkA) is decreased in aged rats and patients with AD. NGF stimulates trkA synthesis, suggesting that NGF signals are not effectively reaching the nucleus of septal cholinergic neurons in aged animals to stimulated trkA synthesis. NGF release mechanisms in hippocampal neurons may be impaired during aging, because septal neurons in aged rats retain the ability to respond to the application of exogenous NGF. This suggests that the problem in the NGF delivery system could be in the releasing hippocampal neuron. However, this does not fully eliminate the possibility the response to NGF in septal neurons is impaired. Preliminary data shows that NGF increases the firing rate of septal neurons in aged rats within minutes of application, but does not change the firing rate of septal neurons in young rats. These data suggest that the physiological response to NGF is altered during aging. Since neither of the age-related biological processes involving NGF described above have been investigated in situ to data, I propose the following specific aims: 1. Does NGF release differ in young versus aged rats? 2. Does the electrophysiological response to NGF differ in septal neurons from young rats versus septal neurons from aged rats? The results from these experiments should prove useful in elucidating the mechanism(s) underlying the problems in NGF delivery during senescence and AD.
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