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: 6299298
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299298
• 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，一个共识已经产生，将神经肽甘丙素联系起来 在正常和病理状态下对胆碱能基底前脑功能的影响 包括公元。大量实验研究表明，甘丙氨酸 体外抑制乙酰胆碱(ACh)水平并损害工作记忆 大鼠，我们和其他人已经证明，甘氨酸能系统经历了 可能改变ACh的残留CBF神经元的增生性反应 神经传递。阿尔茨海默病的胆碱能缺陷发生在疾病的早期 并与这种疾病的严重程度和持续时间相关。 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；增强记忆功能。我们有 在分子签名方面显示出显著的物种差异 人与实验动物大脑中脑血流量的GAL神经支配 包括猴子。这些观察表明，GAL的动物模型- 基于CBF的交互并不能准确地模拟人类的情况。因此， 只有检查人类GAL/CBF系统的研究才可能真正 与阐明相互作用背后的机制有关(S) 在CBF内的GAL和ACH之间。因此，对GAL/ACh的研究 人类CBF内的相互作用将提供更好的理解 阿尔茨海默病胆碱能细胞功能障碍的病理过程 这一子项目的目的是研究病理生理学。 CBF内潜在甘丙素可塑性的变化及其与 阿尔茨海默病认知功能减退的进展。我们将检验这一假设 这种GAL重塑与GAL数量的增加有关 阿尔茨海默病患者脑组织中表达mRNA的神经元。或者，我们将检验这一假设 在CBF内每个神经元的GAL mRNA合成增加 在公元后。我们将确定甘丙素肥大是否与 受体位点数(Bmax)增加或GAL改变 AD患者CBF内的亲和力(结合；Kd)。我们还将测试 关于GAL受体变化具有区域性特异性的假设 AD时CBF内的结合。这些研究将使用神经心理学 检测、放射免疫分析、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 关于独特的甘丙素基底前脑重塑的信息 作为疾病进展的函数的反应。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。