Curcumin improves tau-induced neuronal dysfunction of nematodes
Curcumin improves tau-induced neuronal dysfunction of nematodes
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DOI：
10.1016/j.neurobiolaging.2015.11.004
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发表时间：
2016-03-01
影响因子：
4.2
通讯作者：
Ihara, Yasuo
中科院分区：
文献类型：
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作者：
Miyasaka, Tomohiro;Xie, Ce;Ihara, Yasuo
Tau 蛋白是多种神经退行性疾病发病机制中的关键蛋白，这些神经退行性疾病被归类为 tau 病。由于 tau 蛋白病理的程度与阿尔茨海默病的神经元损失和临床症状密切相关，因此抗 tau 蛋白疗法（如果有的话）可能对广泛的 tau 蛋白病有益。为了了解有关 tau 蛋白病的更多信息，我们开发了一种新型转基因线虫（秀丽隐杆线虫）模型，该模型在所有神经元中表达野生型或 R406W tau 蛋白。表达 tau 蛋白的野生型线虫表现出运动不协调 (Unc) 和神经炎异常。 Tau 蛋白在失去微管的异常神经突中积累。在表达低水平 R406W-tau 的线虫中也发现了类似的异常，但在表达相对水平的野生型 tau 的线虫中却没有发现类似的异常。生化研究表明，tau 蛋白异常磷酸化，但不会形成不溶于去污剂的聚集体。在这些蠕虫中进行的药物筛选发现姜黄素（姜黄中的一种主要植物化学化合物）不仅可以减少 Unc，还可以减少野生型和表达 R406W tau 蠕虫的神经炎异常。我们的观察表明微管稳定介导姜黄素的抗毒性作用。姜黄素对表达 tau 片段的线虫也有效，但它不能阻止 tau 片段二聚体的形成。这些数据表明姜黄素改善了 tau 诱导的神经元功能障碍，该功能障碍与不溶性 tau 聚集体无关。 (C) 2016 年作者。由爱思唯尔公司出版
Tau is a key protein in the pathogenesis of various neurodegenerative diseases, which are categorized as tauopathies. Because the extent of tau pathologies is closely linked to that of neuronal loss and the clinical symptoms in Alzheimer's disease, anti-tau therapeutics, if any, could be beneficial to a broad spectrum of tauopathies. To learn more about tauopathy, we developed a novel transgenic nematode (Caenorhabditis elegans) model that expresses either wild-type or R406W tau in all the neurons. The wild-type tau-expressing worms exhibited uncoordinated movement (Unc) and neuritic abnormalities. Tau accumulated in abnormal neurites that lost microtubules. Similar abnormalities were found in the worms that expressed low levels of R406W-tau but were not in those expressing comparative levels of wild-type tau. Biochemical studies revealed that tau is aberrantly phosphorylated but forms no detergent-insoluble aggregates. Drug screening performed in these worms identified curcumin, a major phytochemical compound in turmeric, as a compound that reduces not only Unc but also the neuritic abnormalities in both wild-type and R406W tau-expressing worms. Our observations suggest that microtubule stabilization mediates the antitoxicity effect of curcumin. Curcumin is also effective in the worms expressing tau fragment, although it does not prevent the formation of tau-fragment dimers. These data indicate that curcumin improves the tau-induced neuronal dysfunction that is independent of insoluble aggregates of tau. (C) 2016 The Authors. Published by Elsevier Inc.