ACHE, CHAT AND CHOLINERGIC NEURONS IN AGING

衰老过程中的疼痛、聊天和胆碱能神经元

• 批准号: 3117784
• 负责人: STEVEN G YOUNKIN
• 金额: $ 14.43万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3117784
• 关键词: Alzheimer's disease; acetylcholinesterase; aging; axon; cerebral cortex; choline acetyltransferase; embryo /fetus tissue /cell culture; hippocampus; histochemistry /cytochemistry; immunochemistry; laboratory rat; messenger RNA; neuronal transport; neuropharmacology; parasympathetic nervous system; pheochromocytoma; prosencephalon

In Alzheimer's disease (AD), there are striking changes in the distribution of choline acetyltransferase (ChAT) and the various molecular forms of acetylcholinesterase (AChE) in the cerebral cortex and nucleus basalis of Meynert (nbM). Our provisional working hypothesis is that these changes are due primarily to altered axonal transport in diseased cholinergic neurons. The major emphasis is on the acquisition of secure information on ChAT, AChE, and the corresponding mRNAs within individual cholinergic neurons and on the development of a system capable of generating similar information on many other proteins and mRNAs. We propose to evaluate the effect of aging and AD on ChAT and the varius molecular forms of AChE (a) on a per neuron basis in cholinergic nbM neurons, (b) at stereotyped locations along the course of cholinergic axons projecting from the nbM, (c) on a per axon basis in cholinergic axons of the fornix, and (d) in cerebral cortex and hippocampus. The effect of aging and AD on ChAT are AChE mRNA in cholinergic nbM neurons will also be evaluated on a per neuron basis. If normal aging causes changes qualitatively similar to those in AD, one may be able to gain considerable insight into the initiating events and the progression of the neuronal pathology in AD by carefully examining non-demented individuals in appropriate age groups. It is primarily for this reason that examination of the effect of aging is proposed. We plan to evaluate the effect of the many drugs that alter fast and/or slow axonal transport on ChAT and the various molecular forms of AChE in cultured PC12 cells. The goal is (a) to support our working hypothesis that impaired axonal transport plays an important role in the neuronal pathology of AD by demonstrating that appropriate impairment of axonal transport causes changed in ChAT and AChE like those observed in AD, and (b) to determine whether changes like those seen in AD occur only after specific perturbations of transport or develop non-specifically. The altered distribution of ChAT and AChE caused by axonal transport inhibitors could result from associated changes in any of the processes that regulate the level of these proteins. To assess this issue, the synthesis, assembly, secretion, and degradation of the various molecular forms of AChE will be assessed in drug-treated and control PC12 cells using techniques previously developed in this laboratory.

在阿尔茨海默病（AD）中，分布发生了显着变化 胆碱乙酰转移酶（ChAT）和各种分子形式的 乙酰胆碱酯酶（AChE）在大脑皮层和基底核 Meynert（nbM）. 我们的临时工作假设是，这些变化 主要是由于病变胆碱能神经轴突运输的改变， 神经元 主要重点是获取安全信息， ChAT、AChE和个体胆碱能神经元内相应的mRNA 神经元和发展的系统能够产生类似的 许多其他蛋白质和mRNA的信息。 我们建议评估 衰老和AD对ChAT和AChE（a）不同分子形式的影响 在胆碱能nbM神经元中基于每个神经元，（B）在定型的 沿着从nbM突出的胆碱能轴突的路线定位， (c)在穹窿的胆碱能轴突中，基于每个轴突，和（d）在穹窿的胆碱能轴突中， 大脑皮层和海马体。 衰老和AD对ChAT的影响 还将在每个神经元上评价胆碱能nbM神经元中的AChE mRNA。 基础 如果正常的衰老导致的变化在性质上与 AD，人们可能能够获得相当多的洞察力， 以及AD中神经元病理学的进展， 在适当的年龄组的非痴呆个体。 主要应由 这是提出检验老化影响的原因。 我们计划 为了评估许多改变快和/或慢轴突的药物的作用， 在培养的PC 12中ChAT和各种分子形式的AChE的转运 细胞 目的是（a）支持我们的工作假设，即受损 轴突运输在AD的神经病理学中起重要作用， 这表明轴突运输的适当损伤会导致 ChAT和AChE的变化与AD中观察到的相似，以及（B）确定 是否像AD中所见的变化只发生在特定的 运输的扰动或非特异性发展。 改变的 轴突运输抑制剂引起的ChAT和AChE分布可能 结果从相关的变化，在任何过程中，调节 这些蛋白质的水平。 为了评估这一问题， 分泌和降解的各种分子形式的乙酰胆碱酯酶将是 使用先前的技术在药物处理和对照PC 12细胞中评估 在这个实验室里开发的。