GALANIN PLASTICITY IN ALZHEIMER'S DISEASE

甘丙肽在阿尔茨海默病中的可塑性

• 批准号: 3123409
• 负责人: ELLIOTT Jay MUFSON
• 金额: $ 13.84万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3123409
• 关键词: Alzheimer's disease; Cebidae; Parkinson's disease; acetylcholine; aging; animal old age; cell type; cellular pathology; dementia; gene expression; growth factor receptors; histology; human tissue; immunocytochemistry; in situ hybridization; innervation; interneurons; juvenile animal; messenger RNA; monoclonal antibody; neural degeneration; neural plasticity; neuroanatomy; neuropeptides; neurotrophic factors; northern blottings; pathologic process; postmortem; prosencephalon; species difference

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.

该提案的总体目标是获得更完整的 了解之间发生的病理变化 大细胞胆碱能神经元和含有甘丙肽的中间神经元和 它们在人类正常老年人的基底前脑内的过程， 阿尔茨海默病 (AD) 和帕金森病 (PD) 痴呆症患者。 由于甘丙肽 对乙酰胆碱有抑制作用，据推测 基底核上含有甘丙肽的过度神经支配 AD 和 PD 中的胆碱能神经元可能在退行性病变中起关键作用 这些过程中胆碱能细胞功能障碍 神经退行性疾病。 为了评估这个假设，我们将 1) 确定甘丙肽合成的 mRNA 的细胞位置 人类基底前脑亚区，2) 确定是否表达 甘丙肽 mRNA 与人类和猴子之间的物种差异相似 报道了基底前脑内的肽甘丙肽 (36), 3) 确定目前未知的其他基底前脑细胞类型是否与 含有甘丙肽的肽表达其mRNA，40确定是否为甘丙肽 胆碱能基底前脑神经元的过度神经支配发生在所有 该区域在阿尔茨海默氏症和帕金森氏痴呆症中的子领域，5) 确定甘丙肽分布是否存在过度神经支配 基底核伴随着甘丙肽 mRNA 的过度表达，并且 6) 判断基底前脑肥厚性甘丙肽是否含有 配置文件支配 ALZ-50 表达元件。 计划中的研究将 利用多克隆甘丙肽抗体（IgM）进行免疫组织化学分析 小鼠单克隆 ALZ-50 抗体和甘丙肽 mRNA 原位杂交。 该提案生成的数据将提供急需的信息 关于神经退行性事件可能发挥关键作用 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建议。 新的药物疗法作为延缓智力的手段 痴呆症恶化。