GALANIN IN ALZHEIMER'S DISEASE

描述：(申请者摘要)最近，一项共识已经达成 产生将神经肽甘丙素与胆碱能基础相联系 包括AD在内的正常和病理状态下的前脑功能(见12， 18、72)。大量实验研究表明甘丙素抑制 乙酰胆碱(ACh)的体外水平(25)并损害工作记忆 大鼠(18，19，32只)。在AD中，我们和其他人已经证明了Galanine能 系统对剩余的CBF神经元进行增生性反应 (12，72)，这可能改变ACh的神经传递。胆碱能缺乏症 AD(20,101)发生在疾病过程的早期(89)，并与 这种疾病的严重程度(102)和持续时间(102)。此外， 大量的动物和临床文献将CBF神经元联系在一起，这 支配大脑皮层和海马体(59)，提高记忆功能(2，4)。 在之前的资助期间，我们展示了一个戏剧性的物种 大脑中脑血流量内GAL神经支配的化学特征差异 人类和实验动物包括猴子之间的差异(9，48)。这些 观察表明，基于GAL的CBF相互作用的动物模型 不要准确地模仿人类的情况。因此，只有调查 检查人类GAL/CBF系统可能真的与 阐明Gal和Gal相互作用的机制(S) CBF内的ACH。因此，对GAL/ACh相互作用的研究 人类的CBF将提供对病理的更多了解 影响阿尔茨海默病胆碱能细胞功能障碍的过程。目的 继续我们正在进行的对 甘丙球蛋白可塑性的病理生理变化 它们与AD患者认知功能障碍的关系。我们将测试 假设GAL重塑与血管内皮细胞数量增加有关 阿尔茨海默病模型大鼠Gal基因表达神经元的数量。或者，我们将 验证这样的假设，即每个细胞的Gal-mRNA合成增加 阿尔茨海默病患者脑血流中的神经元。我们将确定甘丙素是否 肥大与受体数目的增加有关 或CFG内GAL亲和力(结合；Kd)的变化 广告。我们还将测试假设，即存在一个地区性 AD患者脑血流中GAL受体结合变化的特异性。 我们将检验甘丙素高表达与 阿尔茨海默病患者中存在认知障碍。这些研究将 使用原位杂交、受体药理学、放射免疫分析和 神经心理测试程序。从这些数据中产生的数据 研究将提供有关独特的甘丙素基础的新信息 阿尔茨海默病的前脑重塑反应。此外，这些数据可能 建议旨在延缓的药物疗法的途径 阿尔茨海默病的智力衰退。

DESCRIPTION: (Applicant's Abstract) Recently, a consensus has been generated linking the neuropeptide, galanin to cholinergic basal forebrain function in normal and pathologic states including AD (see 12, 18, 72). Numerous experimental studies have shown that galanin inhibits acetylcholine (ACh) levels in vitro (25) and impairs working memory in rats (18, 19, 32). In AD, we and others have shown that galaninergic system undergoes a hyperplasticic response upon remaining CBF neurons (12,72) which may alter ACh neurotransmission. cholinergic deficits in AD (20, 101) occur early in the disease process (89) and correlate with both the severity (102) and duration (102) of this disorder. Moreover, a vast animal and clinical literature connects CBF neurons, which innervate the cortex and hippocampus (59), to memory function (2,4). During the previous funding period we demonstrated a dramatic species difference in the chemical signature of GAL-innervation within the CBF between humans and experimental animals including monkeys (9,48). These observations indicate that animal models of GAL-based CBF interactions do not accurately mimic the human condition. Thus, only investigations examining the human GAL/CBF system may truly be relevant towards elucidating the mechanism(s) underlying the interaction between GAL and ACh within the CBF. Thus, studies of the GAL/ACh interaction within the human CBF will provide greater understanding of the pathologic process(es) affecting cholinergic cell dysfunction in AD. The purpose of this renewal is to continue our ongoing investigation of the pathophysiologic changes underlying galanin plasticity with the CFG and their relation to cognitive dysfunction in AD. We will test the hypothesis that GAL remodeling is associated with an increase in the number of GAL mRNA-expressing neurons in AD. Alternatively, we will test the hypothesis that there is an increase in GAL mRNA synthesis per neuron within the CBF in AD. We will determine whether galanin hypertrophy is associated with an increase in the number of receptor sites (Bmax) or a change in GAL affinity (binding; KD) within the CFG in AD. We will also test the hypothesis that there is a regional specificity of changes in GAL receptor binding within the CBF in AD. We will test the hypothesis that galanin hyperexpression is associated with cognitive impairment among individuals with AD. These studies will use in situ hybridization, receptor pharmacology, radioimmunoassay and neuropsychological testing procedures. The data generated from these studies will provide new information concerning the unique galanin basal forebrain remodeling response in AD. Furthermore, these data may suggest avenues for pharmacological therapies aimed at retarding intellectual deterioration in AD.