PRODUCTION AND ANALYSIS OF APOE TRANSGENIC MICE

阿尔茨海默病(AD)是一种毁灭性的神经疾病 以渐进性痴呆症为特征，影响5%-10%的老年人 65岁以上。遗传因素显然与早期和 这种相关疾病的晚发性家族性形式。晚发性AD的一种形式 已经被证明与19号染色体的近端长臂相连，并且 随后与载脂蛋白E(ApoE)相关。 载脂蛋白E是一种血浆载脂蛋白，参与脂质转运和 新陈代谢。载脂蛋白E是在大脑中产生的，有三种主要的亚型 在已被指定为E2的人类人口中。E3.E4.这些 等位基因出现的频率约为8%、76%和16%， 分别进行了分析。最近，载脂蛋白E4等位基因与一种 晚发性阿尔茨海默病的风险增加已经确定。后续研究 已证明载脂蛋白E2具有保护作用或延缓 广告的开始。不同异构体发挥作用的确切机制 它们的影响尚不清楚。 研究载脂蛋白E发挥作用和作用的机制 载脂蛋白E在脑分子生物学、生理学和新陈代谢中的作用 AWE正在创造载脂蛋白E 2.3和4个转基因小鼠。Cosmid库来自 具有适当载脂蛋白E基因的人类AD患者在 粘粒载体pWE15和SuperCos 1。含有粘粒克隆的Apo E 隔离和限制映射。适当大小的克隆，其中包含 制备并纯化了载脂蛋白E的脑表达控制区。 显微注射法制备载脂蛋白E转基因小鼠的实验研究 手术将使用缺乏功能的载脂蛋白E的ICE进行 基因(Apo E“敲除”小鼠)。缺乏功能正常的小鼠载脂蛋白E的小鼠， 将产生对人类载脂蛋白纯合和杂合的 E2、3、4等位基因。这些小鼠将作为研究的模型系统 载脂蛋白E在脑功能和代谢中的作用及其潜力 在阿尔茨海默氏症中的作用。

Alzheimer's disease *AD) is a devastating neurological disorder characterized by a progressive dementia which affects 5-10% of the elderly over age 65. Genetic factors have clearly been implicated in the early and late-onset familial forms of the linked disease. A form of late-onset AD has been show to be linked to the proximal long arm of chromosome 19 and subsequently associated with Apolipoprotein E (ApoE). Apo E is a plasma apolipoprotein that is involved in lipid transport and metabolism. Apo E is produced in brain and found in three major isoforms in the human population which have been designated E2. E3. E4. These alleles occur at a frequency of approximately 8, 76, and 16 per cent, respectively. Recently, an association between the ApoE4 allele and an increased risk of late-onset AD has been established. Subsequent studies have demonstrated that Apo E2 has a protective effect or delays the age of onset of Ad. The exact mechanism by which the different isoforms exert their effects are as yet unknown. To study the mechanisms by which Apo E exerts its effects and the role which Apo E plays in brain molecular biology, physiology, and metabolism awe are creating Apo E 2. 3. and 4 transgenic mice. Cosmid libraries from human AD patients with the appropriate Apo E genotype were prepared in the cosmid vectors pWE15 and SuperCos 1. Apo E containing cosmid clones were isolated and restriction mapped. Clones of the proper size containing the brain expression control regions for Apo E were produced and purified. Experiments to produce Apo E transgenic mice using microinjection procedures will be carried out using ice which lack a functional Apo E gene (Apo E "knockout" mice). Mice, lacking a functional murine Apo E, will be produced which are homozygous and heterozygous for the human Apo E2, 3 and 4 alleles. These mice will serve as a model system for the study of the role of Apo E in brain function and metabolism and its potential role in Alzheimer's disease.