Central cholinergic function in AChE-deficient mice

AChE 缺陷小鼠的中枢胆碱能功能

• 批准号: 7013960
• 负责人: JOCHEN KLEIN
• 金额: $ 5.86万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013960
• 关键词: Alzheimer' s disease; acetylcholinesterase; aging; choline; cholinesterases; enzyme activity; enzyme inhibitors; enzyme mechanism; extracellular; genetically modified animals; high performance liquid chromatography; hippocampus; hydrolysis; laboratory mouse; microdialysis; thalamus

DESCRIPTION (provided by applicant): Acetylcholinesterase (ACHE) is the enzyme which is responsible for the breakdown of the neurotransmitter, acetylcholine (ACh), in cholinergic synapses. In the brain, ACh subserves important functions e.g. for attention, learning and memory. Central cholinergic neurons which innervate cortex and hippocampus are typically degenerating during Alzheimer's disease; this process is accompanied by attention and memory deficits in Alzheimer patients. In the present proposal, we suggest to investigate central cholinergic functions in genetically modified mice which are deficient for ACHE. These mice have body tremor and are prone to seizures, observations which are compatible with an excess of ACh due to lack of enzymatic breakdown. The first aim of our study is to quantify extracellular levels of ACh in the brain of AChE-deficient mice compared to heterozygous mice and control mice. For this purpose, we will use the microdialysis technique adapted to mice. We will also measure high-affinity choline uptake to determine possible compensatory changes of ACh turnover in cholinergic neurons. However, the fact that AChE-deficient mice are alive suggests that other pathways may exist to break down ACh. Butyrylcholinesterase (BChE), an enzyme associated with glial cells in the brain but of unknown function, is known to hydrolyze ACh at slow rates. We hypothesize that BChE hydrolyzes ACh in AChE-deficient mice thereby making them viable. Our second aim therefore is to test changes of extracellular ACh in the brain upon application of specific inhibitors of AChE or BChE. Our results will show to what extent the brain can compensate for the loss of ACHE; this is also of interest for intoxications of humans with organophosphates (nerve gases). We will also determine to what extent BChE can substitute for AChE in the brain. Our results will show if inhibitors of BChE may be useful for the treatment of Alzheimer's disease. BChE inhibitors would be expected to increase brain ACh in Alzheimer patients in the absence of peripheral cholinergic toxicity thereby improving therapeutic safety.

描述（由申请人提供）：乙酰胆碱酯酶（ACHE）是负责胆碱能突触中神经递质乙酰胆碱（ACh）分解的酶。在大脑中，ACh具有重要的功能，例如注意力，学习和记忆。支配皮层和海马的中央胆碱能神经元在阿尔茨海默病期间典型地退化;该过程伴随着阿尔茨海默病患者的注意力和记忆缺陷。在目前的建议中，我们建议调查中枢胆碱能功能的基因修饰小鼠缺乏乙酰胆碱酯酶。这些小鼠具有身体震颤并且易于癫痫发作，观察结果与由于缺乏酶分解而导致的过量ACh相容。我们研究的第一个目的是定量乙酰胆碱酯酶缺陷小鼠与杂合子小鼠和对照小鼠相比，脑中的乙酰胆碱细胞外水平。为此，我们将使用适用于小鼠的微透析技术。我们还将测量高亲和力胆碱摄取，以确定胆碱能神经元中ACh周转的可能代偿性变化。然而，乙酰胆碱酯酶缺陷小鼠存活的事实表明，可能存在其他途径来分解乙酰胆碱。丁酰胆碱酯酶（BChE）是一种与大脑中的神经胶质细胞相关但功能未知的酶，已知其以缓慢的速率水解乙酰胆碱。我们假设，BChE水解乙酰胆碱酯酶缺乏小鼠，从而使他们的活力。因此，我们的第二个目的是测试应用AChE或BChE的特异性抑制剂后脑中细胞外ACh的变化。我们的研究结果将显示大脑在多大程度上可以补偿乙酰胆碱酯酶的损失;这也是有机磷酸盐（神经毒气）中毒的人感兴趣的。我们还将确定BChE在多大程度上可以替代大脑中的AChE。我们的研究结果将显示BChE抑制剂是否可用于治疗阿尔茨海默病。预期BChE抑制剂在不存在外周胆碱能毒性的情况下增加阿尔茨海默病患者的脑ACh，从而提高治疗安全性。