High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells
High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells
复制标题
高糖迫使连接 ErbB4 表达和 mTOR/S6K 通路的正反馈环路加剧分化 SH-SY5Y 细胞中 tau 过度磷酸化的形成
DOI：
10.1016/j.neurobiolaging.2018.03.023
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发表时间：
2018-07-01
影响因子：
4.2
通讯作者：
Wang, Shan
中科院分区：
文献类型：
--
作者：
Nie, Sheng-Dan;Li, Xin;Wang, Shan
高糖诱导的哺乳动物雷帕霉素靶蛋白(MTOR)的过度激活是tau蛋白过度磷酸化的信号中枢，从而导致糖尿病相关认知功能障碍的发生。HG如何诱导神经元中mTOR的持续激活尚不清楚。ERBB4是受体酪氨酸激酶家族的成员，在神经回路的发育和功能中起着关键作用，与行为缺陷有关。在这里，我们显示了HG诱导的ErbB4在分化的SH-SY5Y细胞以及链脲佐菌素诱导的糖尿病大鼠的原代海马神经元和海马锥体神经元中的过度表达。抑制ErbB4信号通路可阻断HG诱导的mTOR/S6K信号通路的激活，从而抑制tau蛋白过度磷酸化。相反，ErbB4的过表达增加了mTOR/S6K信号的激活，导致tau过度磷酸化，类似于HG处理。我们还证明，HG在mTOR依赖的转录后水平上调ErbB4的表达。综上所述，我们的结果首次证明了在HG条件下，mTOR的持续激活存在正反馈环，涉及过度表达的ErbB4，导致tau过度磷酸化的形成。因此，ErbB4是治疗糖尿病相关神经变性的潜在靶点。(C)2018 Elsevier Inc.保留所有权利。
High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetesassociated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTORdependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration. (C) 2018 Elsevier Inc. All rights reserved.