Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform
Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform
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DOI：
10.1016/s0896-6273(00)81127-7
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发表时间：
1999-11-01
期刊：
影响因子：
16.2
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Ishihara, T;Hong, M;Lee, VMY
丝状tau聚集物是tau病变的标志，例如，与17号染色体相关的帕金森病额颞叶痴呆（FTDP-17）和肌萎缩侧索硬化症/帕金森病-痴呆复合体（ALS/PDC）。由于FTDP-17 tau基因突变改变了tau的水平和功能，我们在转基因（Tg）小鼠的中枢神经系统中过表达最小的人类tau亚型来模拟tau病变。这些小鼠获得了与FTDP-17和ALS/PDC相似的年龄依赖性中枢神经系统病理，包括不溶性、过度磷酸化的tau和由tau免疫反应性细丝形成的亲银性神经元内包裹体。包裹体存在于皮质和脑干神经元中，但在脊髓神经元中最为丰富，在脊髓神经元中，它们与轴突变性、微管（Mis）减少、腹根轴突运输减少以及脊髓胶质细胞增生和运动无力有关。这些Tg小鼠概括了tau病变的关键特征，并为阐明包括阿尔茨海默病（AD）在内的多种tau病变的机制提供了模型。
Filamentous tau aggregates are hallmarks of tauopathies, e.g., frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC). Since FTDP-17 tau gene mutations alter levels/functions of tau, we overexpressed the smallest human tau isoform in the CNS of transgenic (Tg) mice to model tauopathies. These mice acquired age-dependent CNS pathology similar to FTDP-17 and ALS/PDC, including insoluble, hyperphosphorylated tau and argyrophilic intraneuronal inclusions formed by tau-immunoreactive filaments. Inclusions were present in cortical and brainstem neurons but were most abundant in spinal cord neurons, where they were associated with axon degeneration, diminished microtubules (Mis), and reduced axonal transport in ventral roots, as well as spinal cord gliosis and motor weakness. These Tg mice recapitulate key features of tauopathies and provide models for elucidating mechanisms underlying diverse tauopathies, including Alzheimer's disease (AD).