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

TAU 和 APP 在阿尔茨海默病模型中的转基因表达

• 批准号: 7715792
• 负责人: LARY C WALKER
• 金额: $ 3.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715792
• 关键词: Adult; Age-Months; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Axon; Brain; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; Dendrites; Disease; Electrons; Evaluation; Fluorescence; Funding; Grant; Green Fluorescent Proteins; Institution; Localized; Microscopic; Neurons; Pathogenesis; Pathology; Platelet-Derived Growth Factor; Primates; Publications; Rattus; Research; Research Personnel; Resources; Rodent; Saimiri; Source; Subfamily lentivirinae; Transgenes; Transgenic Organisms; Ubiquitin; Ubiquitin C; United States National Institutes of Health; mature animal; neuronal cell body; nonhuman primate; promoter; tau Proteins; tau expression; transgene expression

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们的研究重点是 tau 蛋白和淀粉样前体蛋白 (APP) 之间的相互作用，在啮齿类动物 (大鼠) 和非人灵长类动物 (Saimiri sciureus) 大脑中产生阿尔茨海默病病理学，特别是灵长类动物中的 tau 蛋白。我们已经证明，与成年大鼠中的巨细胞病毒和血小板衍生生长因子启动子相比，泛素 C 启动子始终产生优异的表达。这些发现用于支持在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（出版物，见下文）。绿色荧光蛋白和 tau 蛋白的转基因表达主要位于神经元胞体、轴突和近端树突中，并且在大鼠中直至 18 个月龄仍保持强烈表达。我们还表明，松鼠猴中 tau 蛋白的表达同样会增加。最后，我们最近完成了大鼠 tau 表达的双重荧光和免疫电子显微镜评估。我们的结果表明，慢病毒传递的转基因的持久、局部表达在成年动物中是可行的，这为在生物学优势物种中有效模拟 AD 发病机制提供了独特的机会。