GALANIN PLASTICITY IN ALZHEIMER'S DISEASE

这项建议的总体目标是获得一个更完整的 对两种疾病之间的病理改变的理解 大细胞胆碱能神经元和甘丙素中间神经元和 它们在正常老年人的基底前脑内的突起， 阿尔茨海默病(AD)和帕金森(PD)痴呆症患者。甘丙素 对乙酰胆碱有抑制作用，已有假设 甘丙素在基底核的超神经支配 AD和PD中的胆碱能神经元可能在退行性变中起关键作用 胆碱能细胞功能障碍的潜在突起 神经退行性疾病。为了评估这一假设，我们将1) 确定甘丙素合成的信使核糖核酸在 人的基底前脑各亚区，2)决定是否表达 甘丙素基因与人类和猴子之间的物种差异相似 基底前脑内甘丙肽的报道(36)，3) 确定其他目前未知的基底前脑细胞类型 含有甘丙肽表达其mRNA的多肽，40决定甘丙素是否 急性淋巴细胞白血病的胆碱能基底前脑神经元有超强神经支配 阿尔茨海默氏症和帕金森氏痴呆症的这一区域的亚区，5) 确定甘丙素轮廓的超神经支配是否存在于 基底核伴有甘丙素mRNA的过度表达， 6)确定基底前脑肥大甘丙素是否含有 ALZ-50表达元件的表达谱。计划中的研究将 利用多克隆甘丙素抗体IgM进行免疫组织化学 小鼠单抗ALZ-50与甘丙素mRNA的原位杂交。 这项提案产生的数据将提供急需的信息 关于神经退行性变事件，这可能在 阿尔茨海默病和帕金森病的基底前脑胆碱能变性 痴呆症。此外，这些数据可能为发展提供了途径 作为延缓智力障碍的一种手段的新的药物疗法 痴呆症的恶化。

The overall objective of this proposal is to gain a more complete understanding of the pathologic alterations which occur between magnocellular cholinergic neurons and galanin containing interneurons and their processes within the basal forebrain of human normal aged, Alzheimer's (AD) and Parkinson's (PD) dementia individuals. Since galanin is inhibitory to acetylcholine, it has been hypothesized that hyperinnervation by galanin containing profiles upon nucleus basalis cholinergic neurons in AD and PD may play a key role in the degenerative process(es) underlying cholinergic cell dysfunction in these neurodegenerative disorders. To evaluate this hypothesis we will 1) determine the cellular location of mRNA for galanin synthesis within the human basal forebrain subfields, 2) determine whether the expression of galanin mRNA parallels the species difference between human and monkeys we reported for the peptide galanin within the basal forebrain (36), 3) determine whether other basal forebrain cell types not currently known to contain the peptide galanin express its mRNA, 40 determine whether galanin hyperinnervation to the cholinergic basal forebrain neurons occurs in all subfields of this region in Alzheimer's and Parkinson's dementia, 5) determine whether the hyperinnervation of galanin profiles within the nucleus basalis is accompanied by an over expression of galanin mRNA, and 6) determine whether the basal forebrain hypertrophic galanin containing profiles innervate ALZ-50 expressing elements. The planned studies will utilize immunohistochemistry using a polyclonal galanin antibody, an IgM mouse monoclonal ALZ-50 antibody and galanin mRNA in situ hybridization. The data generated from this proposal will provide much needed information concerning the neurodegenerative events which may play a pivotal role in basal forebrain cholinergic degeneration in Alzheimer's and Parkinson's dementias. Furthermore, these data may suggest avenues for the development of new pharmacological therapies as a means of retarding intellectual deterioration in dementia.