APOE ISOFORMS IN DEVELOPMENT OF AD LIKE PATHOLOGY IN TRANSGENIC MICE

阿尔茨海默病（AD）是最常见的神经退行性疾病，目前影响着美国数百万人。阿尔茨海默病的动物模型提供了最大的希望来破译疾病的过程，并确定和测试潜在的治疗靶点，最终目标是治愈疾病。由于科学研究表明阿尔茨海默病是一种复杂的多基因疾病，因此需要多种模型来充分了解阿尔茨海默病的发病机制并制定治疗方法。本研究的一个主要目标就是建立这样的模型。该研究将确定表达人类载脂蛋白E变体ApoE-2、-3或-4以及人类淀粉样蛋白前体蛋白APPSWED突变的转基因小鼠是否会发生AD特征的神经病理改变。APPSWED突变与一种家族性AD有关，APOE-4等位基因（基因，APOE；蛋白，APOE）的共存可能会加速或恶化这种AD。相反，ApoE-2和ApoE-3可能改善APPSWED转基因小鼠ad样病理的发展。转基因小鼠将在大脑中过度表达这两种人类基因，但不表达小鼠ApoE或APP。在适当的年龄，将对小鼠进行测试，以确定它们是否以及何时会出现阿尔茨海默病的病理特征：记忆丧失、脑代谢减少、灰质减少和/或心室体积增加，以及大脑组织病理学如神经斑块和神经原纤维结。以下假设将被验证：在大脑中表达人载脂蛋白E4 （ApoE-4）和突变淀粉样蛋白前体蛋白APPSWED的转基因小鼠将发展为侵袭性AD，症状早发；表达其他常见载脂蛋白E亚型ApoE-2或ApoE-3以及APPSWED的小鼠将发展为较轻形式的AD。该研究的优势在于：(i)独特而合理地选择了驱动转基因表达的启动子，（ii）首次检测了ApoE-4与APPSWED在转基因小鼠中的作用；这两种蛋白预计会相互作用并增加ad样病理的启动，（iii）第一个比较APOE-2、-3和-4与转基因小鼠APPSWED相互作用的研究，以及（iv）小鼠APOE或APP基因的存在不会使APOE-2、-3和-4与APPSWED表达的影响复杂化或减弱。

Alzheimer's disease (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 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 variants ApoE-2, -3, or -4 and 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 or worsened by the coexistence of the APOE-4 allele (gene, APOE; protein, ApoE). Conversely, ApoE-2 and ApoE-3 may ameliorate the development of AD-like pathology in APPSWED transgenic mice. Transgenic mice will be developed that over-express 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 hypotheses will be tested: Transgenic mice expressing human apolipoprotein E4 (ApoE-4) and mutated amyloid precursor protein, APPSWED, in brain will develop an aggressive form of AD with early onset of symptoms; mice expressing the other common apolipoprotein E isoforms, ApoE-2 or ApoE-3, plus APPSWED will develop less severe forms of AD. Strengths of the study are (i) a unique and rational choice of promoters to drive expression of the transgenes, (ii) the first examination of the contribution of ApoE-4 with APPSWED in a transgenic mouse; the two proteins are expected to interact and augment initiation of AD-like pathology, (iii) the first study to compare interactions of ApoE-2, -3, and -4 with APPSWED in transgenic mice, and (iv) the effects of expression of APOE-2, -3, and -4 and APPSWED will not be complicated or attenuated by the presence of the mouse APOE or APP genes.