LENTIVIRAL-MEDIATED EXPRESSION OF TRANSGENIC BETA-APP AND PRESENILIN IN MONKEYS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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，不一定是研究者所在机构。埃默里大学（耶基斯/神经学）和杰斐逊医学院科学家之间的这个合作项目的目标是创造新的阿尔茨海默病转基因模型？使用慢病毒载体和疾病相关的转基因来研究阿尔茨海默病（AD）病理学。目前的AD转基因小鼠模型概括了该疾病的某些方面，但它们没有发展出人类特有的完整退行性表型。由于阿尔茨海默病的长期和进行性，重要的是转基因在细胞中长时间强烈表达。为此，我们已经表明，泛素启动子产生最好的神经元转基因表达，并且转基因蛋白在大鼠中保持强烈表达长达13个月。最近，我们已经证明，慢病毒表达人tau蛋白的转基因导致在神经元中，在短短3周内出现累积的tau蛋白。在大鼠中进行的有和没有淀粉样前体蛋白（APP）的tau蛋白表达的长期研究正在进行中。此外，在与博士合作蒂莫西阳的耶基斯成像中心，我们已经开始磁共振成像研究松鼠猴在准备的表达？APP和tau转基因在这个物种中，我们预计将产生一个更像人类的AD表型比在小鼠或大鼠中看到的。最后，我们已经开始测试由Goodman和Votaw博士开发的新型化合物，用于在阿尔茨海默病样淀粉样病变的啮齿动物和灵长类动物模型中对老年斑和脑淀粉样血管病进行体内成像。

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. The goal of this collaborative project among Emory (Yerkes/Neurology) and Jefferson Medical College scientists is to create novel transgenic models of Alzheimer ?s disease (AD) pathology using a lentiviral vectors and disease-linked transgenes. Current transgenic mouse models of AD recapitulate some aspects of the disease, but they do not develop the full degenerative phenotype that is unique to humans. Because of the long-term and progressive nature of Alzheimer's disease, it is important for the transgene to be strongly expressed by cells for a long period of time. To this end, we have shown that the ubiquitin promoter yields that best neuronal transgene expression, and that transgenic protein remains strongly expressed for as long as 13 months in rats. More recently, we have demonstrated that lentiviral expression of a transgene for human tau protein results in the appearance, in neurons, of accumulated tau proteins in as little as 3 weeks. Longer term studies of tau expression, with and without the amyloid precursor protein (APP), are underway in rats. In addition, in collaboration with Dr. Timothy Duong of the Yerkes Imaging Center, we have begun magnetic resonance imaging studies of squirrel monkeys in preparation for the expression of the ?APP and tau transgenes in this species, which we anticipate will yield a more human-like AD phenotype than is seen in mice or rats. Finally, we have begun testing novel compounds, developed by Drs. Goodman and Votaw, for imaging senile plaques and cerebral amyloid angiopathy in vivo in rodent and primate models of Alzheimer-like amyloid pathology.