Miyasaka Tomohiro, Xie Ce, Yoshimura Satomi, Shinzaki Yuki, Yoshina Sawako, Kage-Nakadai Eriko, Mitani Shohei, Ihara Yasuo
Faculty of Medical and Life Sciences, Department of Neuropathology, Doshisha University, Kyotanabe-shi, Kyoto, Japan.
Faculty of Medical and Life Sciences, Department of Neuropathology, Doshisha University, Kyotanabe-shi, Kyoto, Japan.
Neurobiol Aging. 2016 Mar;39:69-81. doi: 10.1016/j.neurobiolaging.2015.11.004. Epub 2015 Dec 1.
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.
Tau蛋白是多种神经退行性疾病发病机制中的关键蛋白，这些疾病被归类为tau蛋白病。由于tau蛋白病变的程度与阿尔茨海默病中神经元丢失的程度和临床症状密切相关，因此任何抗tau蛋白疗法都可能对广泛的tau蛋白病有益。为了更多地了解tau蛋白病，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。表达野生型tau蛋白的线虫表现出不协调运动（Unc）和神经突异常。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蛋白的线虫中也发现了类似的异常，但在表达相当水平野生型tau蛋白的线虫中未发现。生化研究表明，tau蛋白被异常磷酸化，但未形成不溶于去污剂的聚集体。在这些线虫中进行的药物筛选确定姜黄素是姜黄中的一种主要植物化学成分，它不仅能减少野生型和表达R406W tau蛋白的线虫中的Unc，还能减少神经突异常。我们的观察结果表明，微管稳定介导了姜黄素的抗毒性作用。姜黄素在表达tau片段的线虫中也有效，尽管它不能阻止tau片段二聚体的形成。这些数据表明，姜黄素改善了tau蛋白诱导的神经元功能障碍，这种功能障碍与tau蛋白的不溶性聚集体无关。
