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

疼痛，聊天，

• 批准号: 2049584
• 负责人: STEVEN G YOUNKIN
• 金额: $ 22.07万
• 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 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2049584
• 关键词: Alzheimer's disease; PC12 cells; RNA splicing; aging; amyloid proteins; antiserum; brain cell; carboxyl group; cerebrospinal fluid; chemical cleavage; choline acetyltransferase; chromatography; electrophoresis; gene expression; human tissue; immunocytochemistry; laboratory rabbit; membrane proteins; messenger RNA; neurochemistry; nucleic acid sequence; parasympathetic nervous system; protease inhibitor; protein sequence; proteins; proteolysis; purine /pyrimidine metabolism; scintillation counter; solubility; tissue /cell culture; transfection; western blottings

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，这种分布有显著的变化