Deng Haoyue, Mi Man-Tian
Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, 30th Gaotanyan Main Street, Shapingba District, Chongqing, 400038, People's Republic of China.
Neurochem Res. 2016 Sep;41(9):2367-79. doi: 10.1007/s11064-016-1950-9. Epub 2016 May 14.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of β-amyloid peptide (Aβ) and loss of neurons. Resveratrol (RSV) is a natural polyphenol that has been found to be beneficial for AD through attenuation of Aβ-induced toxicity in neurons both in vivo and in vitro. However, the specific underlying mechanisms remain unknown. Recently, autophagy was found to protect neurons from toxicity injuries via degradation of impaired proteins and organelles. Therefore, the aim of this study was to determine the role of autophagy in the anti-neurotoxicity effect of RSV in PC12 cells. We found that RSV pretreatment suppressed β-amyloid protein fragment 25-35 (Aβ25-35)-induced decrease in cell viability. Expression of light chain 3-II, degradation of sequestosome 1, and formation of autophagosomes were also upregulated by RSV. Suppression of autophagy by 3-methyladenine abolished the favorable effects of RSV on Aβ25-35-induced neurotoxicity. Furthermore, RSV promoted the expression of sirtuin 1 (SIRT1), auto-poly-ADP-ribosylation of poly (ADP-ribose) polymerase 1 (PARP1), as well as tyrosyl transfer-RNA (tRNA) synthetase (TyrRS). Nevertheless, RSV-mediated autophagy was markedly abolished with the addition of inhibitors of SIRT1 (EX527), nicotinamide phosphoribosyltransferase (STF-118804), PARP1 (AG-14361), as well as SIRT1 and TyrRS small interfering RNA transfection, indicating that the action of RSV on autophagy induction was dependent on TyrRS, PARP1 and SIRT1. In conclusion, RSV attenuated neurotoxicity caused by Aβ25-35 through inducing autophagy in PC12 cells, and the autophagy was partially mediated via activation of the TyrRS-PARP1-SIRT1 signaling pathway.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征在于β-淀粉样肽（Aβ）的积累和神经元的丧失。白藜芦醇（RSV）是一种天然多酚，已发现其通过在体内和体外减轻Aβ诱导的神经元毒性而对AD有益。然而，具体的潜在机制仍然未知。最近，发现自噬通过降解受损蛋白质和细胞器来保护神经元免受毒性损伤。因此，本研究的目的是确定自噬在RSV对PC12细胞的抗神经毒性作用中的作用。我们发现RSV预处理可抑制β-淀粉样蛋白片段25-35（Aβ25-35）诱导的细胞活力下降。RSV还上调了轻链3-II的表达、聚集体蛋白1的降解和自噬体的形成。3-甲基腺嘌呤抑制自噬消除了RSV对Aβ25-35诱导的神经毒性的有利影响。此外，RSV促进了沉默调节蛋白1（SIRT1）的表达、聚（ADP-核糖）聚合酶1（PARP1）的自动多聚ADP-核糖基化以及酪氨酰转移RNA（tRNA）合成酶（TyrRS）的表达。然而，添加SIRT1抑制剂（EX527）、烟酰胺磷酸核糖基转移酶（STF-118804）、PARP1抑制剂（AG-14361）以及SIRT1和TyrRS小干扰RNA转染后，RSV介导的自噬明显被消除，这表明RSV对自噬诱导的作用依赖于TyrRS、PARP1和SIRT1。总之，RSV通过在PC12细胞中诱导自噬减轻了Aβ25-35引起的神经毒性，并且自噬部分是通过TyrRS-PARP1-SIRT1信号通路的激活介导的。
