TRANSGENIC EXPRESSION OF TAU AND APP IN MODELS OF ALZHEIMER'S DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 我们的研究集中在tau蛋白和淀粉样前体蛋白（APP）之间的相互作用，在啮齿动物（大鼠）和非人灵长类动物（松鼠猴）大脑中产生阿尔茨海默病的病理，特别强调在灵长类动物中的tau蛋白。我们已经证明，在成年大鼠中，与巨细胞病毒和血小板源性生长因子启动子相比，泛素C启动子始终产生上级表达。这些发现用于支持在阿尔茨海默病的新转基因大鼠模型中使用泛素作为启动子（出版物，下文）。绿色荧光蛋白和tau蛋白的转基因表达主要定位于神经元胞体、轴突和近端树突，并且在大鼠中持续到18个月龄。我们还表明，松鼠猴中tau蛋白的表达也可以类似地增加。最后，我们最近完成了对大鼠tau蛋白表达的双重荧光和免疫电镜评估。我们的研究结果表明，持久的，局灶性表达的慢病毒传递的转基因在成年动物是可行的，提供了一个独特的机会，有效地模拟AD发病机制的生物优势物种。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our studies focused on interactions between tau protein and the amyloid precursor protein (APP) in producing Alzheimer's disease pathology in the rodent (rat) and nonhuman primate (Saimiri sciureus) brain, with particular emphasis on tau protein in primates. We have shown that the ubiquitin C promoter produces consistently superior expression compared to the cytomegalovirus and platelet-derived growth factor promoters in adult rats. These findings were used to support the use of ubiquitin as the promoter in a new transgenic rat model of Alzheimer's disease (publications, below). Transgene expression of both green fluorescent protein and tau protein is localized primarily in neuronal somata, axons, and proximal dendrites, and remains intense up to 18 months of age in rats. We have also shown that tau expression can be similarly increased in squirrel monkeys. Finally, we recently completed dual fluorescence and immuno-electron microscopic evaluations of tau expression in rats. Our results show that enduring, focal expression of lentivirus-delivered transgenes is feasible in adult animals, presenting a unique opportunity to efficiently model AD pathogenesis in biologically advantageous species.