MOLECULAR MECHANISMS FOR NGF DURING AGING

随着今天西方世界预期寿命的增加， 与年龄相关神经变性疾病的发病率也有所增加 戏剧性地。前脑胆碱能系统内的神经传递是 衰老受损，这个系统也是主要目标之一， 阿尔茨海默病（AD）。关于这种胆碱能物质的一个重要理论 变性表明神经生长因子的传递受损 (NGF)从海马神经元到基底前脑隔胆碱能神经元 神经元这一过程包括一系列步骤， 以有效地递送NGF。这些步骤包括： 海马神经元合成和释放NGF;与NGF结合 隔胆碱能神经元上的受体;结合的受体必须触发 适当的第二信使系统;和逆行运输的 NGF/NGF受体复合物与隔神经元索马胞体的结合， 影响转录。目前尚不清楚海马神经元是否释放NGF， 神经元随着年龄的增长而变化，目前尚不清楚是否有NGF介导的反应， 隔神经元内的神经元随年龄变化。这两个问题将是 在拟议的实验中进行了研究。神经生长因子的合成没有出现 由于NGF mRNA和蛋白质水平在细胞中没有耗尽， 老年大鼠或AD患者的海马。然而， 老年大鼠和/或大鼠高亲和力NGF受体（trkA）减少 AD患者然而，高亲和力NGF受体的表达， （trkA）在老年大鼠和AD患者中降低。NGF刺激trkA 合成，这表明NGF信号没有有效地到达 老年动物隔核胆碱能神经元对trkA刺激的反应 合成.海马神经元中的NGF释放机制可能受损 在衰老过程中，因为老年大鼠的隔神经元保留了 对外源性NGF的应用有反应。这表明 神经生长因子输送系统的问题可能是在释放海马 neuron.然而，这并不能完全消除这种可能性。 隔神经元对NGF的反应受损。初步数据显示， 神经生长因子增加老年大鼠隔神经元的放电频率 分钟的应用，但不改变间隔放电率 年轻老鼠的神经元这些数据表明， 神经生长因子在衰老过程中会发生变化。因为年龄相关的 已经研究了涉及上述NGF的生物过程 在原地数据，我建议以下具体目标：1。神经生长因子 年轻大鼠与老年大鼠的释放量有何不同？2.电生理学是否 大鼠隔区神经元对NGF的反应不同 老年大鼠的神经元这些实验的结果应该可以证明 有助于阐明神经生长因子问题的潜在机制 在衰老和AD期间递送。

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.