Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies
Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies
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DOI：
10.1523/jneurosci.2691-05.2005
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发表时间：
2005-10-12
影响因子：
5.3
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Higuchi, M;Zhang, B;Lee, VMY
少突胶质细胞（OLG）中丰富的丝状tau包涵体是神经退行性tau蛋白病的标志，包括散发性皮质基底节变性和遗传性额颞叶痴呆伴与染色体17相关的帕金森综合征（FTDP-17）。然而，这些tau蛋白病中神经变性的机制尚不清楚，部分原因是缺乏用于实验分析的动物模型。我们通过使用2（'），3'-环核苷酸3 '-磷酸二酯酶启动子产生仅在OLG中表达人tau的转基因（Tg）小鼠来解决这个问题。由于OLG中的人tau表达，特别是表达FTDP-17人P301 L突变tau的那些，在这些Tg小鼠中出现了丝状OLG tau内含物。值得注意的是，髓鞘和轴突的结构破坏之前出现的硫黄素-S阳性tau包涵体在OLG中，但轴突运输的损伤发生得更早，而运动缺陷随后发展，特别是在Tg小鼠与最高的tau表达水平。这些数据表明，OLG中tau蛋白的积累导致神经退行性变，我们推断它们是通过破坏轴突运输来实现的。我们认为，类似的缺陷也可能发生在散发性和遗传性人类tau蛋白病与OLG tau病理。
Abundant filamentous tau inclusions in oligodendrocytes (OLGs) are hallmarks of neurodegenerative tauopathies, including sporadic corticobasal degeneration and hereditary frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). However, mechanisms of neurodegeneration in these tauopathies are unclear in part because of the lack of animal models for experimental analysis. We address this by generating transgenic (Tg) mice expressing human tau exclusively in OLGs using the 2('), 3'-cyclic nucleotide 3'-phosphodiesterase promoter. Filamentous OLG tau inclusions developed in these Tg mice as a result of human tau expression in OLGs, especially those expressing the FTDP-17 human P301L mutant tau. Notably, structural disruption of myelin and axons preceded the emergence of thioflavin-S positive tau inclusions in OLGs, but impairments in axonal transport occurred even earlier, whereas motor deficits developed subsequently, especially in Tg mice with the highest tau expression levels. These data suggest that the accumulation of tau in OLG cause neurodegeneration, and we infer they do so by disrupting axonal transport. We suggest that similar defects may also occur in sporadic and hereditary human tauopathies with OLG tau pathologies.