Complement C3a receptor antagonist attenuates tau hyperphosphorylation via glycogen synthase kinase 3β signaling pathways
Complement C3a receptor antagonist attenuates tau hyperphosphorylation via glycogen synthase kinase 3β signaling pathways
复制标题
补体 C3a 受体拮抗剂通过糖原合成酶激酶 3β 信号通路减弱 tau 过度磷酸化
DOI：
10.1016/j.ejphar.2019.02.020
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发表时间：
2019-05-05
影响因子：
5
通讯作者：
Li, Gang
中科院分区：
文献类型：
--
作者：
Junjie, Hu;Yang, Yang;Li, Gang
由过度磷酸化的tau蛋白聚集而成的神经元缠结是阿尔茨海默病（AD）的主要病理特征。补体C3（或C3 a）是补体系统的核心组分，并且与AD病理过程相关。然而，目前还不清楚C3 a或C3 a受体是否对tau磷酸化有任何影响。在这项研究中，我们发现SH-SY 5 Y细胞暴露于冈田酸（OA）降低细胞活力并诱导tau蛋白过度磷酸化。C3 a受体拮抗剂SB 290157可减轻这些作用，并在OA处理的SH-SY 5 Y细胞中通过C3 a受体siRNA进一步验证。另外，SB 290157对糖原合成酶激酶3 β（GSK 3 β）活性有明显抑制作用，但对蛋白磷酸酶2AC亚基（PP 2Ac）和细胞周期蛋白依赖性激酶5（CDK 5）活性无明显影响。我们的研究结果表明，C3 a受体在通过GSK 3 β信号通路调节tau磷酸化中的独特作用，并表明C3 a受体可能是治疗AD的可行靶点。
Neurofibrillary tangles aggregated from hyperphosphorylated tau protein are the main pathological feature of Alzheimer's disease (AD). Complement C3 (or C3a) is the core component of the complement system and is associated with AD pathological processes. However, it remains unclear whether C3a or the C3a receptor has any effect on tau phosphorylation. In this study, we found that exposure of SH-SY5Y cells to okadaic acid (OA) decreased cell viabilities and induced tau hyperphosphorylation. These effects were alleviated by C3a receptor antagonist SB290157 and were further validated by C3a receptor siRNA in OA-treated SH-SY5Y cells. In addition, our results demonstrated that SB290157 markedly inhibited the activities of glycogen synthase kinase 3 beta (GSK3 beta), but had no effect on protein phosphatase 2A C subunit (PP2Ac) and cyclin-dependent kinases 5 (CDK5). Our findings here indicate the unique role of the C3a receptor in regulating tau phosphorylation via GSK3 beta signaling pathways and suggest that the C3a receptor may be a viable target for treating AD.