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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们的研究集中在啮齿动物(大鼠)和非人灵长类动物(Saimiri Scureus)脑中tau蛋白与淀粉样前体蛋白(APP)在产生阿尔茨海默病病理过程中的相互作用，特别是灵长类动物中的tau蛋白。我们已经证明，与巨细胞病毒和血小板衍生生长因子启动子相比，泛素C启动子在成年大鼠中持续产生更高的表达。这些发现被用来支持在一种新的阿尔茨海默病转基因大鼠模型中使用泛素作为启动子(发表如下)。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，并在18月龄前保持强烈表达。我们还证明tau在松鼠猴中的表达也可以类似地增加。最后，我们最近完成了对tau在大鼠体内表达的双重荧光和免疫电子显微镜评估。我们的结果表明，在成年动物中持续、集中表达慢病毒传递的转基因是可行的，这为在生物优势物种中有效地模拟AD发病机制提供了独特的机会。

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.