Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice
Accumulation of filamentous tau in the cerebral cortex of human tau R406W transgenic mice
复制标题
DOI：
10.1016/s0002-9440(10)62274-2
复制
发表时间：
2005-02-01
影响因子：
6
通讯作者：
Westaway, D
中科院分区：
文献类型：
--
作者：
Ikeda, M;Shoji, M;Westaway, D
Tau基因的错义突变导致常染色体显性额颞部。与17号染色体相关的痴呆症和帕金森症(FTDP-17)，一种以进行性人格变化、痴呆症和帕金森症为特征的疾病。脑额颞叶明显萎缩，伴有大量tau积聚，伴有神经原纤维缠结和神经细胞丢失。使用仓鼠Pron蛋白基因表达载体，我们产生了几个独立的转基因(TG)小鼠，表达与FTDP-17相关的R406W突变的最长形式的人四重复tau。TgTauR406W 21807系显示tau在6个月龄时开始在海马区和杏仁体积聚，随后扩散到皮质和皮质下区域。累积的tau被磷酸化，泛素化，构象改变，亲银，不溶于肌氨基。观察GSK-3β的激活和Tau对小鼠星形胶质细胞的诱导。星形胶质细胞增多症和小胶质细胞增多症与显著的tau积聚相关。电子显微镜检查显示有直丝的存在。行为测试显示，10到12个月大的婴儿出现运动障碍和渐进性获得记忆，丧失记忆力。这些发现表明，TgTauR406w小鼠将是研究额颞叶痴呆和阿尔茨海默病(AD)等其他疾病的有用模型。
Missense mutations of the tau gene cause autosomal dominant frontotemporal. dementia and parkinsonism linked to chromosome 17 (FTDP-17), an illness characterized by progressive personality changes, dementia, and parkinsonism. There is prominent frontotemporal lobe atrophy of the brain accompanied by abundant tau accumulation with neurofibrillary tangles and neuronal cell loss. Using a hamster prion protein gene expression vector, we generated several independent lines of transgenic (Tg) mice expressing the longest form of the human four-repeat tau with the R406W mutation associated with FTDP-17. The TgTauR406W 21807 line showed tau accumulation beginning in the hippocampus and amygdala at 6 months of age, which subsequently spread to the cortices and subcortical, areas. The accumulated tau was phosphorylated, ubiquitinated, conformationally changed, argyrophilic, and sarcosyl-insoluble. Activation of GSK-3beta and astrocytic induction of mouse tau were observed. Astrogliosis and microgliosis correlated with prominent tau accumulation. Electron microscopic examination revealed the presence of straight filaments. Behavioral tests showed motor disturbances and progressive acquired memory, loss between 10 to 12 months of age. These findings suggested that TgTauR406w mice would be a useful model in the study of frontotemporal dementia and other tauopathies such as Alzheimer's disease (AD).