GALANIN IN ALZHEIMER'S DISEASE

（申请人的摘要）最近，已经达成共识， 产生的连接神经肽，甘丙肽胆碱能基础 正常和病理状态包括AD的前脑功能（参见12， 18、72）。 大量的实验研究表明甘丙肽抑制 乙酰胆碱（ACh）水平体外（25）和损害工作记忆， 大鼠（18，19，32）。 在AD中，我们和其他人已经表明， 系统在剩余的CBF神经元上经历增生性反应 (12，72），这可能会改变乙酰胆碱的神经传递。 胆碱能缺陷 AD（20，101）发生在疾病过程的早期（89），并与 这种疾病的严重性（102）和持续时间（102）。 此外，委员会认为， 大量的动物和临床文献将CBF神经元连接起来， 神经支配皮层和海马（59），记忆功能（2，4）。 在上一个资助期间，我们展示了一个引人注目的物种， CBF内GAL神经支配化学特征的差异 人类和实验动物（包括猴子）之间的关系（9，48）。 这些 观察表明，基于GAL的CBF相互作用的动物模型 并不能准确地模拟人类的状况 因此，只有调查 研究人类GAL/CBF系统可能确实与 阐明GAL与 CBF内的ACh。 因此，研究体内GAL/ACh相互作用 人类CBF将提供更多的了解病理 影响AD中胆碱能细胞功能障碍的过程。 目的 这次更新的目的是继续我们正在进行的调查， 病理生理学变化潜在的甘丙肽可塑性与CFG和 与AD认知功能障碍的关系 我们将测试 假设GAL重塑与 AD中GAL mRNA表达神经元的数量。 或者，我们将 测试假设，即有增加GAL mRNA的合成， AD时CBF内的神经元。 我们将确定甘丙肽 肥大与受体数量的增加有关。 位点（Bmax）或在CFG内GAL亲和力（结合; KD）的变化， AD. 我们还将测试假设，有一个区域 AD中CBF内GAL受体结合变化的特异性。 我们将检验甘丙肽高表达与 AD患者中的认知障碍。 这些研究将 使用原位杂交、受体药理学、放射免疫测定和 神经心理学测试程序。 从这些生成的数据 研究将提供关于独特的甘丙肽基础的新信息， AD的前脑重塑反应。 此外，这些数据可能 提出了药物治疗的途径， AD中的智力退化。

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.