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Abstract：
Tauopathies include a variety of neurodegenerative diseases associated with the pathological aggregation of hyperphosphorylated tau, resulting in progressive cognitive decline and motor impairment. The underlying mechanism for motor deficits related to tauopathy is not yet fully understood. Here, we use a novel transgenic tau mouse line, Tau 58/4, with enhanced neuron-specific expression of P301S mutant tau to investigate the motor abnormalities in association with the peripheral nervous system. Using stationary beam, gait, and rotarod tests, motor deficits were found in Tau 58/4 mice already 3 months after birth, which deteriorated during aging. Hyperphosphorylated tau was detected in the cell bodies and axons of motor neurons. At the age of 9 and 12 months, significant denervation of the neuromuscular junction in the extensor digitorum longus muscle was observed in Tau 58/4 mice, compared to wild-type mice. Muscle hypotrophy was observed in Tau 58/4 mice at 9 and 12 months. Using electron microscopy, we observed ultrastructural changes in the sciatic nerve of 12-month-old Tau 58/4 mice indicative of the loss of large axonal fibers and hypomyelination (assessed by g-ratio). We conclude that the accumulated hyperphosphorylated tau in the axon terminals may induce dying-back axonal degeneration, myelin abnormalities, neuromuscular junction denervation, and muscular atrophy, which may be the mechanisms responsible for the deterioration of the motor function in Tau 58/4 mice. Tau 58/4 mice represent an interesting neuromuscular degeneration model, and the pathological mechanisms might be responsible for motor signs observed in some human tauopathies.
摘要：
Tau病变包括多种与过度磷酸化tau的病理聚集相关的神经退行性疾病，导致进行性认知下降和运动障碍。与tau蛋白病变相关的运动缺陷的潜在机制尚未完全了解。这里,我们使用一种新的转基因tau小鼠系，Tau58/4，增强P301S突变型tau的神经元特异性表达，以研究与周围神经系统相关的运动异常。使用静止光束，步态,和旋转杆测试，在出生后3个月的Tau58/4小鼠中发现了运动缺陷，在老化过程中恶化。在运动神经元的细胞体和轴突中检测到过度磷酸化的tau。在9个月和12个月大的时候，在Tau58/4小鼠中观察到趾长伸肌中神经肌肉接头的显着去神经支配，与野生型小鼠相比。在Tau58/4小鼠中在9个月和12个月时观察到肌肉肥大不足。使用电子显微镜，我们观察到12个月大的Tau58/4小鼠坐骨神经的超微结构变化，表明大轴突纤维丢失和髓鞘减少（通过g比评估）。我们得出的结论是，轴突末端积累的过度磷酸化tau可能会导致垂死的轴突变性，髓鞘异常，神经肌肉接头神经支配,肌肉萎缩,这可能是导致Tau58/4小鼠运动功能恶化的机制。Tau58/4小鼠代表了一个有趣的神经肌肉变性模型，病理机制可能是在某些人类tau蛋白病中观察到的运动体征的原因。
