GALANIN REMODELING IN THE PROGRESSION OF ALZHEIMER'S DISEASE

最近，一个共识已经产生连接的神经肽，甘丙肽 正常和病理状态下胆碱能基底前脑功能 包括AD。 大量的实验研究表明甘丙肽 在体外抑制乙酰胆碱（ACh）水平， 大鼠，我们和其他人已经表明，甘丙肽能系统经历了一个 可能改变ACh的剩余CBF神经元的增生反应 神经传递 AD的胆碱能缺陷发生在疾病的早期 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神经元连接起来， 神经支配皮层和海马体;记忆功能。 我们有 证明了一个显着的物种差异的分子签名， 人与实验动物脑血流内GAL神经支配的比较 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地模拟人类状况。 因此，在本发明中， 只有研究人类GAL/CBF系统的研究才可能真正 有助于阐明相互作用的机制 GAL和ACh之间的相互作用。 因此，GAL/ACh的研究 人类CBF内的相互作用将提供更好的理解， AD中影响胆碱能细胞功能障碍的病理过程。 该子项目的目的是研究 CBF内甘丙肽可塑性的变化及其与 AD中认知能力下降的进展。 我们将检验这个假设 GAL重塑与GAL数量的增加有关， AD中表达mRNA的神经元。 或者，我们将测试假设 CBF内每个神经元的GAL mRNA合成增加， 在AD中。 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假说 在AD的CBF内结合。 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 提出了药物治疗的途径， AD中的智力退化。

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.