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Hyperphosphorylation and aggregation of tau protein, and neuronal death

tau 蛋白的过度磷酸化和聚集以及神经元死亡

基本信息

批准号：
12210005
负责人：
IHARA Yasuo
金额：
$ 92.29万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12210005/
关键词：
Alzheimer's disease Tau Neurofibrillary tangles Neuronal death

项目摘要

Discovery of various mutations in the tau gene among the families affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) suggests gain-of-toxic function of wild-type or mutant tau as the mechanism for extensive neuronal loss. To learn about the role of tau in the tauopathy, we have generated animal models that express FTDP-17 mutant (P301L or R406W) tau.1.We established transgenic mice expressing prion promoter-driven P301L mutant tau. The brains were sampled from those mice at various ages (3, 6, 12, 20, and 24 months) and analyzed by either biochemical or immunohistochemical methods. However, transgene-derived alterations, such as degeneration of neurons and deposition of tau, were not observed up to 24 months.2.We generated transgenic nematode (Caenorhabditis elegans) expressing wild-type or mutant (P301L and R406W) tau in the touch (mechanosensory) neurons. Whereas the worm expressing wild-type tau showed only a small decrease in the touch response across the lifespan, the worm expressing mutant tau displayed a large and progressive decrease. When the touch neurons lost their function, neuritic abnormalities were prominent, and microtubular loss became remarkable in the later stage. A substantial fraction of degenerating neurons developed tau accumulation in the cell body and neuronal processes. This neuronal dysfunction is not related to the apoptotic process because little recovery from touch abnormality was observed in the ced-3 or ced-4-deficient background. Expression of GSK3 brought about slight deterioration in the touch response, while expression of HSP70 led to some improvement.

在与17号染色体相关的额颞叶痴呆和帕金森病（FTDP-17）受影响的家族中，tau基因的各种突变的发现表明，野生型或突变型tau的毒性功能获得是广泛神经元丢失的机制。为了了解tau在tau病中的作用，我们建立了表达FTDP-17突变体（P301L或R406W） tau的动物模型。我们建立了表达朊病毒启动子驱动的P301L突变体tau的转基因小鼠。从这些小鼠的不同年龄（3、6、12、20和24个月）中抽取大脑样本，并通过生化或免疫组织化学方法进行分析。然而，转基因衍生的改变，如神经元变性和tau沉积，在24个月内未被观察到。我们在触摸（机械感觉）神经元中产生了表达野生型或突变型（P301L和R406W） tau的转基因线虫（秀丽隐杆线虫）。在整个生命周期中，表达野生型tau蛋白的蛔虫在触摸反应中只表现出少量的减少，而表达突变型tau蛋白的蛔虫则表现出大幅度的、渐进的减少。当触觉神经元丧失功能时，神经突异常突出，后期微管丢失明显。相当一部分退化的神经元在细胞体和神经元过程中产生tau积累。这种神经元功能障碍与凋亡过程无关，因为在ced-3或ced-4缺乏的背景下，几乎没有观察到触觉异常的恢复。GSK3的表达使触摸反应轻微恶化，而HSP70的表达使触摸反应有所改善。