GALANIN REMODELING IN THE PROGRESSION OF ALZHEIMER'S DISEASE

阿尔茨海默病进展中的甘丙肽重塑

• 批准号: 6295529
• 负责人: ELLIOTT Jay MUFSON
• 金额: $ 15.71万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295529
• 关键词: Alzheimer's disease; aging; autoradiography; galanin; gene expression; human tissue; in situ hybridization; neuropharmacology; neuropsychological tests; neurotransmitter receptor; pathologic process; postmortem; protein biosynthesis; radioimmunoassay; receptor binding

Recently, a consensus has been generated linking the neuropeptide, galanin to cholinergic basal forebrain function in normal and pathologic states including AD. Numerous experimental studies have shown that galanin inhibits acetylcholine (ACh) levels in vitro and impairs working memory in rats, we and others have shown that galaninergic systems undergoes a hyperplastic response upon remaining CBF neurons which may alter ACh neurotransmission. Cholinergic deficits in AD occur early in the disease process and correlate with both the severity and duration of this disorder. Moreover, a vast animal and clinical literature connects CBF neurons, which innervate the cortex and hippocampus; to memory function. We have demonstrated a dramatic species difference in the molecular signature of GAL-innervation within the CBF between humans and experimental animals including monkeys. 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 mechanisms (s) underlying the interaction between GAL and ACh within athe CBF. Thus, studies of the GAL/ACh interaction within the human CBF will provide a greater understanding of the pathologic process(es) affecting cholinergic cell dysfunction in AD. The purpose of this subproject is to investigate the pathophysiologic changes underlying galanin plasticity within the CBF and their relation to the progression of cognitive decline 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 ina the number of receptor sites (Bmax) or a change in GAL affinity (binding; KD) within the CBF 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. These studies will use neuropsychological testing, radioimmunoassay, in situ hybridization and receptor pharmacology procedures. The data generated from these studies will provide new information concerning the unique galanin basal forebrain remodeling response as a function of disease progression. Furthermore, these data may suggest avenues for pharmacological therapies aimed at retarding intellectual deterioration in AD.

最近，已经产生了一个共识，将神经肽Galanin连接起来 在正常和病理状态下的胆碱能基底脑功能 包括广告。 许多实验研究表明Galanin 在体外抑制乙酰胆碱（ACH）水平，并损害工作记忆 大鼠，我们和其他人都表明，甘霉素能系统发生A 剩余的CBF神经元后的增生反应可能会改变ACH 神经传递。 AD的胆碱能缺陷发生在该疾病早期 过程并与该疾病的严重程度和持续时间相关。 此外，庞大的动物和临床文献将CBF神经元连接起来，该神经元 支配皮质和海马；到内存功能。 我们有 在分子特征的分子特征中显示出巨大的物种差异 人与实验动物之间CBF内的gal毒 包括猴子。 这些观察结果表明，GAL的动物模型 基于CBF的相互作用不能准确模仿人类状况。 因此， 只有检查人类gal/cbf系统的调查才能真正是 与阐明相互作用的基础机制有关 在ACBF内的GAL和ACH之间。 因此，GAL/ACH的研究 人类CBF内部的互动将提供对 影响AD中胆碱能细胞功能障碍的病理过程（ES）。 该副本的目的是研究病理生理 CBF内的Galanin可塑性的改变及其与之的关系 AD认知能力下降的进展。 我们将检验假设 GAL重塑与GAL数量增加有关 AD中表达mRNA的神经元。 或者，我们将检验假设 CBF内每个神经元的GAL mRNA合成有所增加 在广告中。 我们将确定加拉宁肥大是否与 增加受体位点（BMAX）的数量或GAL的变化 AD中CBF内的亲和力（绑定； KD）。 我们还将测试 假设GAL受体发生变化的区域特异性 在AD中的CBF内结合。 这些研究将使用神经心理学 测试，放射免疫测定，原位杂交和受体药理学 程序。 这些研究产生的数据将提供新的 有关独特的Galanin基础前脑重塑的信息 反应是疾病进展的函数。 此外，这些数据可能 建议用于延迟的药理学疗法的途径 AD的智力恶化。