AMINERGIC FUNCTION IN AGING AND ALZHEIMERS DISEASE

该计划项目资助更新申请有两个主要的研究重点： (1)去甲肾上腺素能神经递质的中枢神经和心血管变化 2）伴随衰老的胆碱能机制， 可能是与年龄相关的认知功能下降的基础。 一个基本 目标，历史上的主要重点，在过去六年， 该计划，继续是年龄相关的机制的研究 中枢神经系统的药理学特性发生变化， 心血管系统 我们将研究与年龄相关的药物变化， 在实验动物模型和人类中的反应性。 这种变化的分子机制，在受体方面， 信使分子和突触前功能的调节将是 利用动物和人体组织进行生化研究。 生理 将使用电记录技术检查相关性， 体内计时电流法和电刺激。 形态 将评估神经元和非神经元元素中的相关性。 将利用组织移植来确定固有与 任何与年龄相关的中枢神经变化的外在性质。 主要 要追求的假设是CNS中的突触前和/或突触后变化 突触回路或外周自主神经效应器机制将 是肾上腺素能药物反应性的许多变化的基础， 衰老 我们的第二个研究重点是中枢神经突触的研究， 这些变化可能是认知功能障碍的基础，代表了主要的新的 研究计划，如果。 该计划的主要工作将是 致力于研究胆碱能回路中与年龄相关的变化， 神经营养因子和移植物的作用， 记忆，如长时程增强（LTP）和推定的分子 LTP的机制，如突触蛋白的磷酸化。 再次 行为、电生理、电化学和 将使用生物化学方法。 我们的努力将涵盖广泛的 从分子遗传学方法到 神经营养剂，参与使用神经生长因子的临床试验 脑内输注给阿尔茨海默病患者。

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.