APOE 4 & ABINFLUENCE ON DEVELOPMENT OF ALZHEIMERS DIS

阿兹海默症(AD)，最常见的神经退行性疾病。 目前在美国影响着数百万人。动物 AD模型为破译AD的进程提供了最大的希望 疾病，并确定和测试潜在的治疗靶点 治愈这种疾病的最终目标。因为科学研究 揭示了家族性阿尔茨海默病是一种复杂的、多基因的疾病，更 完全了解阿尔茨海默病的发病机制需要一个模型 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。这项研究将确定转基因 表达人载脂蛋白E变异体ApoE-4和/或a的小鼠 人类淀粉样前体蛋白突变体APPSWED将出现 阿尔茨海默病特有的神经病理改变。APPSWED 突变与一种形式的家族性AD有关，这可能是 ApoE-4(apoE基因； 蛋白质ApoE)。这两种人类蛋白的结合 在转基因小鼠的大脑中进行靶向可能会产生一种 尤其是AD的积极模式。转基因小鼠将成为 在大脑中过度表达这两个人类基因，但表达 没有鼠标ApoE或应用程序。在适当的年龄，这些老鼠将被测试为 确定他们是否以及何时出现AD的病理特征： 记忆力丧失，大脑新陈代谢下降，灰质和/或 脑室容量增加和神经炎等脑组织病理学改变 斑块和神经原纤维缠结。下面的假设是 测试：突变的fl-淀粉样蛋白和大脑之间的相互作用 人载脂蛋白E-4亚型将在体内转基因动物的脑内出现 老鼠。相互作用将导致认知变化和 类似阿尔茨海默病的脑部病理改变。 所开发的独特的转基因小鼠品系可能提供一种特别的 攻击性AD模型以及其他不太严重的AD模型。优势 这项研究的主要内容是：(I)选择独特而理性的宣传片来 推动转基因的表达，(Ii)这项研究的终极 转基因小鼠将携带不是一个，而是两个人类AD相关基因 有望相互作用并增强启动的转基因 以及(Iii)APOE-4和APOE-4基因表达的影响。 AppsSWED不会因为存在 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.