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，将神经肽甘丙肽联系起来已达成共识 正常和病理状态下的胆碱能基础前脑功能 包括AD。 大量实验研究表明甘丙肽 抑制体外乙酰胆碱 (ACh) 水平并损害工作记忆 我们和其他人已经证明，甘丙肽能系统经历了大鼠 对剩余 CBF 神经元的增生反应可能会改变 ACh 神经传递。 AD 中的胆碱能缺陷出现在疾病早期 过程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 神经元联系起来，这 支配皮质和海马体；达到记忆功能。 我们有 证明了分子特征的显着物种差异 人类和实验动物之间 CBF 内的 GAL 神经支配 包括猴子。 这些观察结果表明，GAL-的动物模型 基于 CBF 的相互作用并不能准确地模拟人类的状况。 因此， 只有检查人类 GAL/CBF 系统的研究才可能真正有效 与阐明相互作用背后的机制相关 CBF 内的 GAL 和 ACh 之间。 因此，GAL/ACh 的研究 人类 CBF 内的相互作用将提供更好的理解 影响 AD 胆碱能细胞功能障碍的病理过程。 该子项目的目的是研究病理生理学 改变 CBF 内潜在的甘丙肽可塑性及其与 AD 认知能力下降的进展。 我们将检验假设 GAL 重塑与 GAL 数量增加相关 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 合成增加 在公元。 我们将确定甘丙肽肥大是否与 受体位点数量 (Bmax) 增加或 GAL 变化 AD 中 CBF 内的亲和力（结合；KD）。 我们还将测试 GAL 受体变化存在区域特异性的假设 AD 中 CBF 内的结合。 这些研究将使用神经心理学 测试、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 有关独特的甘丙肽基底前脑重塑的信息 反应作为疾病进展的函数。 此外，这些数据可能 建议旨在延缓的药物治疗途径 AD 中的智力退化。