Sun Yue, Xiao Qian, Luo Cheng, Zhao Yuxing, Pu Die, Zhao Kexiang, Chen Jinliang, Wang Meili, Liao Zhiyin
Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, China.
Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, China.
Exp Cell Res. 2017 Oct 15;359(2):312-318. doi: 10.1016/j.yexcr.2017.07.032. Epub 2017 Aug 10.
Diabetic encephalopathy (DE) is one of the most common complications of diabetes. The major pathological variations include neurofibrillary tangles (NFTs), which are caused by tau hyperphosphorylation, and senile plaques (SPs) consisting of amyloid β- protein(Aβ) deposits. In recent years, DE research studies have focused on exploring the activation of the inflammatory signaling pathway in immune cells. Toll-like receptor 9 (TLR9) is well known to regulate the inflammatory reactions in immune processes. During the tau hyperphosphorylation process, TLR9 in microglia plays bidirectional roles. However, no studies have clearly demonstrated the relationship between TLR9 and tau hyperphosphorylation in neurons. Based on our experiments, we found significant increase in TLR9 expression in neurons and an increase in tau hyperphosphorylation in high-glucose media. However, these alterations can be reversed by TLR9 inhibitor. Furthermore, we specifically inhibited the activation of P38mitogenactivated protein kinase(P38MAPK) and found an effective decrease in tau hyperphosphorylation. This effect is likely related to Unc93b1. Meanwhile, High glucose levels can induce neuronal apoptosis via the TLR9 signaling pathway. Our studies are the first to reveal that high glucose can regulate tau hyperphosphorylation and neuronal apoptosis via TLR9-P38MAPK signaling pathway. These findings provide a new method for studying the mechanism underlying DE.
糖尿病性脑病（DE）是糖尿病最常见的并发症之一。主要病理变化包括由tau蛋白过度磷酸化引起的神经原纤维缠结（NFTs），以及由淀粉样β蛋白（Aβ）沉积组成的老年斑（SPs）。近年来，DE研究主要集中在探索免疫细胞中炎症信号通路的激活。Toll样受体9（TLR9）在免疫过程中调节炎症反应，这一点广为人知。在tau蛋白过度磷酸化过程中，小胶质细胞中的TLR9发挥双向作用。然而，尚无研究明确证实神经元中TLR9与tau蛋白过度磷酸化之间的关系。基于我们的实验，我们发现高糖培养基中神经元TLR9表达显著增加，tau蛋白过度磷酸化也增加。然而，这些改变可被TLR9抑制剂逆转。此外，我们特异性抑制P38丝裂原活化蛋白激酶（P38MAPK）的激活，发现tau蛋白过度磷酸化有效降低。这种效应可能与Unc93b1有关。同时，高糖水平可通过TLR9信号通路诱导神经元凋亡。我们的研究首次揭示高糖可通过TLR9-P38MAPK信号通路调节tau蛋白过度磷酸化和神经元凋亡。这些发现为研究DE的发病机制提供了一种新方法。
