ACHE, CHAT, & CHOLINERGIC NEURONS IN AGING & ALZHEIMER'S

在阿尔茨海默病(AD)中，分布有显著变化 胆碱乙酰转移酶(ChAT)及其各种分子形式 大脑皮层和基底核中的乙酰胆碱酯酶 Meynert(NBM)。我们的临时工作假设是，这些变化 主要是由于疾病胆碱能神经元轴突运输的改变 神经元。主要的重点是获取安全的信息 ChAT、AChE和个体胆碱能体内相应的mRNAs 以及开发一种能够产生类似的 许多其他蛋白质和mRNAs的信息。我们建议评估 衰老和阿尔茨海默病对ChAT及其各种分子形式的影响(A) 在胆碱能NBM神经元中以神经元为单位，(B)在刻板印象中 从NBM投射的胆碱能轴突的位置， (C)穹隆胆碱能轴突中以轴突为单位； 大脑皮层和海马体。衰老和AD对ChAT的影响是 胆碱能NBM神经元中的AchE mRNA也将在每个神经元上进行评估 基础。如果正常老化引起的变化在质量上类似于 公元一年，人们也许能够对启蒙事件有相当大的了解 通过仔细观察AD的神经元病理进展 适当年龄段的非痴呆者。它主要是为了 这就是为什么提出要考察老龄化的影响。我们计划 评估多种改变快速和/或减慢轴突的药物的效果 胆碱酯酶在PC12细胞上的转运及多种分子形式的胆碱酯酶 细胞。目标是(A)支持我们的工作假设，即损害 轴突运输在阿尔茨海默病的神经元病理中起重要作用 证明轴突运输的适当损害会导致 像在AD中观察到的那样，在聊天和疼痛中发生变化，以及(B)确定 像AD中看到的那些变化是否仅在特定的 运输的扰动或发展的非专一性。被更改的 轴突运输抑制剂引起的ChAT和AChE的分布可能 是由任何调节 这些蛋白质的水平。为了评估这个问题，合成、组装、 分泌和降解各种分子形式的乙酰胆碱酯酶 使用先前的技术对药物治疗和对照PC12细胞进行评估 在这个实验室里研发的。

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.