Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors.
Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors.
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DOI：
10.1038/srep24933
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发表时间：
2016-04-26
影响因子：
4.6
通讯作者：
Jo C
中科院分区：
文献类型：
--
作者：
Kim S;Choi KJ;Cho SJ;Yun SM;Jeon JP;Koh YH;Song J;Johnson GV;Jo C
磷酸化tau蛋白的神经元积累在阿尔茨海默病（AD）的发病机制中起着关键作用。在这里，我们检查了非瑟酮（一种黄酮醇）对tau水平的影响。用非瑟酮处理皮质细胞或原代神经元导致磷酸化tau水平显著降低。此外，在gsk -3β诱导的活性tau聚集模型中，非瑟汀降低了萨科齐不溶性tau的水平。然而，无论非瑟汀治疗与否，tau激酶和磷酸酶（如蛋白磷酸酶2A）的活性都没有差异。非西汀激活自噬，同时激活转录因子EB （TFEB）和Nrf2转录因子。包括TFEB在内的自噬激活可能是由于非瑟酮介导的哺乳动物雷帕霉素复合物1靶点（mTORC1）抑制，因为p70S6激酶和4E-BP1的磷酸化水平在非瑟酮存在下降低。事实上，非甾酮诱导的磷酸化tau降解被自噬-溶酶体途径的化学抑制剂所减弱。结果表明，非瑟酮通过TFEB和Nrf2激活的自噬途径降低磷酸化tau的水平。我们的结果表明，非瑟酮作为一种潜在的预防和治疗AD的候选药物应该进一步评估。
The neuronal accumulation of phosphorylated tau plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Here, we examined the effect of fisetin, a flavonol, on tau levels. Treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau. In addition, fisetin decreased the levels of sarkosyl-insoluble tau in an active GSK-3β-induced tau aggregation model. However, there was no difference in activities of tau kinases and phosphatases such as protein phosphatase 2A, irrespective of fisetin treatment. Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors. The activation of autophagy including TFEB is likely due to fisetin-mediated mammalian target of rapamycin complex 1 (mTORC1) inhibition, since the phosphorylation levels of p70S6 kinase and 4E-BP1 were decreased in the presence of fisetin. Indeed, fisetin-induced phosphorylated tau degradation was attenuated by chemical inhibitors of the autophagy-lysosome pathway. Together the results indicate that fisetin reduces levels of phosphorylated tau through the autophagy pathway activated by TFEB and Nrf2. Our result suggests fisetin should be evaluated further as a potential preventive and therapeutic drug candidate for AD.