AMINERGIC FUNCTION IN AGING AND ALZHEIMERS DISEASE

本次计划项目续批申请有两大研究重点： (1)去甲肾上腺素能中枢神经和心血管变化的研究 伴随衰老的传递和2)胆碱能机制 可能是与年龄相关的认知功能下降的原因。一种基本的 目标，从历史上看，过去六年的主要重点是 该计划，继续研究与年龄相关的机制 中枢神经药理特性的变化和 心血管系统。我们将研究药物中与年龄相关的变化 在实验动物模型和人类中的反应性。这个 从受体的角度来看，这种变化的分子机制是 信使分子和突触前功能的调节 使用动物和人体组织进行生物化学研究。生理学 将使用电子记录技术来检查相关性，在 活体计时电流法和电刺激。形态 将评估神经性和非神经性元素的相关性。 组织移植将被用来确定固有的与 任何与年龄相关的中枢神经变化的外在性质。少校 需要进行的假设是中枢神经系统中突触前和/或突触后的变化 突触回路或在外周自主神经效应机制中 肾上腺素能药物反应性的许多变化是由 衰老。我们的第二个研究重点是中枢神经突触 可能导致认知功能障碍的变化，代表着主要的新 研究计划的主动性。这一计划的主要努力将是 致力于研究与衰老相关的胆碱能回路的变化， 神经营养因子和移植的作用，细胞模型 记忆，如长时程增强(LTP)和假定的分子 LTP的机制，如突触蛋白的磷酸化。又来了 行为、电生理、电化学和 将利用生化方法。我们的努力将涵盖广泛的 光谱范围从分子遗传学方法到研究 神经营养物质，参与使用NGF的临床试验 阿尔茨海默病患者的脑内输液。

This program project grant renewal application has two major research foci: (1) studies on central nervous and cardiovascular changes in noradrenergic transmission that accompany senescence and 2) cholinergic mechanisms that may underlie age-related declines in cognitive function. One basic objective, historically the major focus during the previous six years of the program, continues to be the study of the mechanism of age-related changes in the pharmacological properties of the central nervous and cardiovascular systems. We will study age-related changes in drug responsiveness in both experimental animal models and in man. The molecular mechanisms for such changes, in term of receptors, of second messenger molecules and of the regulation of presynaptic function will be pursued biochemically using both animal and human tissues. Physiological correlates will be examined using techniques of electrical recording, in vivo chronoamperometry, and electrical stimulation. Morphological correlates in both neuronal and non-neuronal elements will be evaluated. Tissue transplantation will be utilized to determined the intrinsic versus extrinsic nature of any age-related central nervous changes. The major hypothesis to be pursued is that per-and/or postsynaptic changes in CNS synaptic circuitry or in peripheral autonomic neuroeffector mechanism will underlie many of the alterations in adrenergic drug responsivity seen with aging. Our second research focus, studies on central nervous synaptic changes which may underlie cognitive dysfunction, represents the major new research initiative if the program. Major efforts in this program will be devoted to examination of aged-related changes in cholinergic circuitry, effects of neuronotrophic factors and transplants, cellular models of memory such as long-term potentiation (LTP) and putative molecular mechanisms of LTP such as phosphorylation of synaptic proteins. Again in admixture of behavioral, electrophysiological, electrochemical and biochemical approaches will be utilized. Our efforts will cover a broad spectrum ranging from molecular genetic approaches to studies of neuronotrophic agents, to participation on a clinical trial using NGF infusion intracerebrally into patients with Alzheimers Disease.