DEVELOPING A NON-HUMAN PRIMATE MODEL OF ALZHEIMER 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。 阿尔茨海默病是一种独特的人类老年疾病，会慢慢破坏大脑功能。最近的研究表明，这种疾病与大脑中特定蛋白质的积聚有关；其中一种是淀粉样蛋白(A？)，这是形成老年斑的淀粉样前体蛋白(APP)的一部分，另一种是tau蛋白，它在神经细胞中过度积累。已经建立了转基因小鼠模型来研究这些蛋白质，但没有一个小鼠模型完全类似于人类阿尔茨海默病。例如，A？免疫疗法在降低A？和改善小鼠行为方面非常成功，但在患有阿尔茨海默病的人类中，同样的治疗导致了脑部炎症和萎缩，而这在小鼠模型中并不明显。这些严重的副作用阻碍了这种有希望的治疗方法在人类身上的应用。 在本报告所述期间，我们培育了两只转基因AD猴子。我们目前正在进行纵向研究，包括认知行为测试、核磁共振、代谢物常规采血、基因组和蛋白质组谱研究。此外，我们还建立了同时表达APPswe/ind和人类tau基因的恒河猴胚胎干细胞系。这些干细胞系是多能的，能够在体外分化为神经细胞类型。正在进行的努力是进一步确定这些干细胞系的特征，并将它们开发为AD研究的细胞模型。

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. Alzheimer's disease is a uniquely human disorder of old age that slowly destroys brain function. Recent research has shown that the disease is associated with a buildup of specific proteins in the brain; one of these proteins is amyloid-¿ (A¿), a fragment of the amyloid-precursor protein (APP) that forms senile plaques, and the other is the protein tau, which accumulates excessively in nerve cells. Transgenic mouse models have been created to study these proteins, but no mouse model fully resembles human Alzheimer's disease. For example, A¿-immunization therapy is remarkably successful in reducing A¿ and improving behavior in mice, but in humans with Alzheimer's disease, the same treatment resulted in brain inflammation and shrinkage that were not evident in mouse models. These serious side-effects have impeded the application of this promising treatment to humans. During the reporting period, we generated two transgenic AD monkeys. We are currently performing longitudinal studies including cognitive behavioral testing, MRI, routine blood collection for metabolite, genome and proteome profiling study. In addition, we have established rhesus embryonic stem cell lines that express both APPswe/ind and human tau genes. These stem cell lines are pluripotent and capable of differentiating into neuronal cell types in vitro. Ongoing effort is to further characterize such stem cell lines and develop them as a cell model for AD research.