APOE 4 & ABINFLUENCE ON DEVELOPMENT OF ALZHEIMERS DIS

阿兹海默症（AD）是最常见的神经退行性疾病。 目前影响着美国数百万人。 动物 AD模型提供了破译过程的最佳希望， 疾病和识别和测试潜在的治疗目标， 治愈疾病的最终目标。 自从科学研究 揭示了家族性AD是一种复杂的多基因疾病， 要完全理解AD的发病机制，需要不止一种模型 并开发治疗方法。 本研究的一个主要目标是 就是开发这样的模型。 这项研究将确定是否转基因 表达人载脂蛋白E变体ApoE-4和/或 人类淀粉样蛋白前体蛋白的突变体，APPSWED将开发 AD特征性的神经病理学改变。 APPSWED 突变与家族性AD的一种形式有关， APOE-4（基因APOE; 蛋白ApoE）。 这两种人类蛋白质的组合大约 在转基因小鼠的大脑中， 特别是AD的攻击性模型。 转基因小鼠将是 开发了在大脑中过度表达两种人类基因，但表达 无小鼠ApoE或APP。在适当的年龄，将测试小鼠以 确定他们是否以及何时发展出AD的病理特征： 记忆丧失、脑代谢降低、灰质减少和/或 脑室容量增加和脑组织病理学，如神经炎 斑块和神经纤维缠结。 以下假设将是 测试：突变型fl-淀粉样蛋白和 人ApoE-4同种型将在转基因小鼠脑中体内出现， 小鼠 这些互动将导致认知的变化， 大脑中的病理改变将类似于AD的标志。 开发的独特的转基因小鼠品系可能提供一种特别的 侵袭性AD模型以及其他不太严重的AD模型。 优势 研究的主要目的是：（1）促进剂的选择是一种独特而合理的选择， （二）研究的最终目的 转基因小鼠将携带不是一个，而是两个人类AD相关基因。 转基因，预期相互作用和增强启动 AD样病理学的影响，和（iii）APOE-4和 AppsSWED不会因存在 小鼠APOE或APP基因。

Azheimer's (AD), the most common neurodegenerative disorder. currently affects several million people in the United States. Animal models of AD provide the best hope of deciphering the course of the disease and identifying and testing potential therapeutic targets with the ultimate goal of curing the disease. Since scientific studies have revealed that familial AD is a complex, polygenic disorder, more than one model is required to fully understand the pathogenesis of AD and develop therapeutic approaches. A major goal of the present study is to develop such models. The study will determine if transgenic mice expressing the human apolipoprotein E variant ApoE-4 and/or a mutant of human amyloid precursor protein, APPSWED will develop neuropathological alterations characteristic of AD. The APPSWED mutation is associated with a form of familial AD which may be accelerated and worsened by the coexistence of APOE-4 (gene APOE; protein ApoE). The combination of these two human proteins appro priately targeted in brains of transgenic mice may produce a particularly aggressive model for AD. Transgenic mice will be developed that overexpress the two human genes in brain, but express no mouse ApoE or APP. At appropriate ages, the mice will be tested to determine if and when they develop pathological hallmarks of AD: memory loss, decreased brain metabolism, decreased gray matter and/or increased ventricular volume and brain histopathology such as neuritic plaques and neurofibrillary tangles. The following hypothesis will be tested: Brain interactions between a mutant fl-amyloid protein and the human ApoE-4 isoform will occur in vivo in brains of transgenic mice. The interactions will lead to cognitive changes and pathological alterations in brain that will resemble hallmarks of AD. The unique transgenic mouse lines developed may furnish a particularly aggressive AD model as well as other less severe AD models. Strengths of the study are (I) a unique and rational choice of promo tors to drive expression of the transgenes, (ii) the study's ultimate transgenic mouse will carry not one, but two human AD-associated transgenes which are expected to interact and augment initiation of AD-like pathology, and (iii) the effects of expression of APOE-4 and AppsSWED will not be complicated or attenuated by the presence of the mouse APOE or APP genes.