Cortical neuronal and glial pathology in TgTauP301L transgenic mice -: Neuronal degeneration, memory disturbance, and phenotypic variation
Cortical neuronal and glial pathology in TgTauP301L transgenic mice -: Neuronal degeneration, memory disturbance, and phenotypic variation
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DOI：
10.2353/ajpath.2006.051250
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发表时间：
2006-10-01
影响因子：
6
通讯作者：
Shoji, Mikio
中科院分区：
文献类型：
--
作者：
Murakami, Tetsuro;Paitel, Erwan;Shoji, Mikio
在动物模型中重现tau蛋白病理是神经退行性疾病研究的长期目标。我们培育了转基因（TgTau(P301L)）小鼠，在最长形式的tau （2N, 4R）中表达与17号染色体相关的额颞叶痴呆伴帕金森病（FTPD-17）突变。TgTau（P301L）小鼠出现丰富的病理，包括神经元前缠结、大量grallyas - braak阳性的神经原纤维缠结和大脑额颞区、脑干的胶质原纤维缠结，以及较小程度的脊髓缠结。这些特征伴有神经胶质瘤、神经元丧失和脑萎缩。积聚的tau被过度磷酸化，构象改变，泛素化，和萨科齐不溶性，电镜显示波浪形细丝。老年TgTau（P301L）小鼠表现出海马依赖和独立行为模式的损伤，其损伤与tau病理的存在和不溶性tau蛋白的水平密切相关。我们得出结论，TgTau（P301L）小鼠重现了FI'DP-17患者的大量表型变异和病理谱。在这些小鼠中鉴定改变tau表型的遗传和/或环境因素可能会揭示调节人类tau病的因素。这些转基因小鼠可能有助于FTDP-17和其他以四重复tau积累为特征的疾病的治疗发展，如阿尔茨海默病、皮质基底变性和进行性核上性麻痹。
Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTau(P301L)) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTau(P301L) mice developed florid pathology including neuronal pretangles, numerous Grallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTau(P301L) mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTau(P301L) mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FI'DP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.