Guo Haibiao, Wang Haitao, Wang Canmao, Cheng Yufang, Zou Zhengqiang, Li Yiwen, Wu Jingang, Xu Jiangping
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.
J Mol Neurosci. 2015 Jun;56(2):519-27. doi: 10.1007/s12031-015-0572-z. Epub 2015 May 13.
Amyloid plaques and neurofibrillary tangles are the key pathological features of Alzheimer's disease (AD). Studies have shown that C-reactive protein (CRP) increases during inflammatory reactions and, therefore, has been associated with AD. However, there is no published report relating the impact of CRP to the regulation of tau phosphorylation. In the present study, we investigated the effects of CRP on the phosphorylation of tau protein in SH-SY5Y cells. Treatment of cells with CRP (5, 10, 20 μg/ml) resulted in neurotoxicity and apoptosis, as was observed by MTT assay and Hoechst staining, respectively. Western blot analysis showed that CRP, in a time- and concentration-dependent manner, induced the phosphorylation of tau at Ser202 and ser396 in SH-SY5Y cells. Phosphorylation of Akt (Ser473) and GSK3β (Ser9) were decreased by CRP treatment, whereas phosphorylation of ERK and p38 were not affected. Pharmacological inhibition of GSK3β reversed the effects induced by CRP, viz., cytotoxicity, apoptosis, and tau phosphorylation. Herein, we present a novel mechanism of cell death following CRP insult, which activates tau hyperphosphorylation by regulating GSK3β activity. CRP could potentially be used as an important pathological factor for the therapeutic intervention of AD.
淀粉样斑块和神经原纤维缠结是阿尔茨海默病（AD）的关键病理特征。研究表明，C反应蛋白（CRP）在炎症反应期间会升高，因此与AD有关。然而，尚无已发表的报告阐述CRP对tau蛋白磷酸化调节的影响。在本研究中，我们调查了CRP对SH-SY5Y细胞中tau蛋白磷酸化的影响。用CRP（5、10、20μg/ml）处理细胞分别导致神经毒性和凋亡，这通过MTT试验和Hoechst染色观察到。蛋白质免疫印迹分析表明，CRP以时间和浓度依赖性方式诱导SH-SY5Y细胞中Ser202和ser396位点的tau蛋白磷酸化。CRP处理降低了Akt（Ser473）和GSK3β（Ser9）的磷酸化，而ERK和p38的磷酸化未受影响。GSK3β的药理学抑制逆转了CRP诱导的细胞毒性、凋亡和tau蛋白磷酸化等效应。在此，我们提出了CRP损伤后细胞死亡的一种新机制，即通过调节GSK3β活性激活tau蛋白过度磷酸化。CRP可能作为AD治疗干预的一个重要病理因素。
