AGING AND DEMENTIA: CHOLINERGIC NEURON BIOCHEMISTRY

衰老和痴呆：胆碱能神经元生物化学

• 批准号: 3376740
• 负责人: PETER P DAVIES
• 金额: $ 29.59万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3376740
• 关键词: Alzheimer's disease; affinity chromatography; aging; amyloid proteins; animal old age; anticholinergic agent; blood; brain; cerebral cortex; cerebrospinal fluid; choline acetyltransferase; chromosome disorders; gene expression; hippocampus; histochemistry /cytochemistry; human old age (65+); human tissue; immunochemistry; innervation; juvenile animal; laboratory mouse; mental disorder diagnosis; molecular cloning; monoclonal antibody; neuroanatomy; neurochemistry; nucleic acid sequence; parasympathetic nervous system; postmortem; psychobiology; surface antigens

The goal of these investigations is to provide insight into the etiology and pathogenesis of the cholinergic dysfunction of Alzheimer's Disease and some other dementing disorders, and to attempt to use some of the information obtained to improve the accuracy of differential diagnosis. In the next project period we plan to expand our studies of ventral forebrain cholinergic neurons innervating cerebral cortex and hippocampus, because it is now well established that these cells dysfunction and perhaps degenerate in cases of Alzheimer's Disease and some, but not all, other dementing disorders. Using monoclonal antibodies to proteins apparently unique to these cells, we will test the hypothesis that dysfunction of these cells can be detected by reduced concentrations of these antigens, and will determine if they are present in detectable amounts in blood and spinal fluid, and whether or not there are quantitative or qualitative abnormalities that can be used as aids to the differential diagnosis of Alzheimer's Disease. Because of the well-established links between Alzheimer's Disease and Down's Syndrome, we will test the hypothesis that there are quantitative or qualitative abnormalities of proteins from chromosome 21 in patients with Alzheimer's Disease. If any of the above studies reveal consistent qualitative or quantitative differences between Alzheimer patients and normals, we will clone the gene or genes coding for the appropriate proteins, and carry out studies of gene structure and expression. A speculative model for the pathogenesis of cholinergic dysfunction has been constructed, and this has led to the development of two simple and testable hypotheses. We will test these by screening blood, spinal fluid and brain tissue from appropriate cases for the presence of endogenous compounds with muscarinic antagonist-like properties, or the ability inhibit high affinity choline uptake systems.

这些调查的目的是提供对病因的见解 以及阿尔茨海默氏病的胆碱能功能障碍的发病机理和 其他一些痴呆症，并尝试使用一些 获得的信息是为了提高鉴别诊断的准确性。 在 下一个项目期我们计划扩大对腹前脑的研究 胆碱能神经元支配大脑皮层和海马，因为它 现在已经很好地确定了这些细胞功能障碍，甚至可能退化 在阿尔茨海默氏病以及一些但不是全部痴呆症的情况下 疾病。 使用对蛋白质的单克隆抗体显然是独有的 这些细胞，我们将测试这些细胞功能障碍的假设 可以通过这些抗原的浓度降低来检测到 确定它们是否存在于血液和脊柱中的可检测量 流体，以及是否存在定量或定性 可以用作鉴别诊断的异常 阿尔茨海默氏病。 因为 阿尔茨海默氏病和唐氏综合症，我们将检验以下假设。 蛋白质有定量或定性异常 阿尔茨海默氏病患者的21染色体。 如果以上任何一个 研究揭示了一致的定性或定量差异 阿尔茨海默氏症患者和正常人，我们将克隆编码的基因或基因 适当的蛋白质，并进行基因结构和 表达。 胆碱能发病机理的投机模型 功能障碍已建成，这导致了 两个简单且可检验的假设。 我们将通过筛选血液来测试这些， 适当病例的脊髓液和脑组织 具有毒蕈碱拮抗剂样特性的内源性化合物，或 能力抑制高亲和力胆碱吸收系统。