Abstract：
Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). Our recent report has revealed the neuroprotective effect of dihydroartemisinin (DHA) on mice overexpressing human Tau (hTau) in the hippocampus by enhancing O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) modification. However, whether DHA can improve synaptic and cognitive function in hTau transgenic mice by specifically promoting Tau O-GlcNAcylation is still unclear. Here, we introduced hTau transgenic mice, a more optimal tauopathy model, to study the effect of DHA on Tau O-GlcNAcylation. We reported that DHA treatment alleviated the deficits of hippocampal CA1 LTP and spatial learning and memory in the Barnes maze and context fear conditioning tests in hTau transgenic mice. Mechanically, we revealed that DHA exerted a significant protective effect by upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation. Through molecular docking, we found a stable binding between DHA and O-GlcNAc transferase (OGT). We further reported that DHA treatment had no effect on the expression of OGT, but it promoted OGT nuclear export, thereby enhancing OGT-mediated Tau O-GlcNAcylation. Taken together, these results indicate that DHA exerts neuroprotective effect by promoting cytoplasmic translocation of OGT and rebuilding the balance of Tau O-GlcNAcylation/phosphorylation, enhancing O-GlcNAcylation of Tau, suggesting that DHA may be a potential therapeutic agent against tauopathy.
摘要：
Tau病是几种神经退行性疾病的统称，其特征在于细胞内过度磷酸化的微管相关蛋白Tau（P-tau）的积累。我们最近的报告揭示了双氢青蒿素（DHA）通过增强O-连接-N-乙酰氨基葡萄糖（O-GlcNAcylation）修饰对海马中过表达人Tau（hTau）的小鼠的神经保护作用。然而,DHA是否可以通过特异性促进TauO-GlcNAcylation改善hTau转基因小鼠的突触和认知功能尚不清楚。这里,我们引入了hTau转基因小鼠，更理想的tau蛋白病变模型，研究DHA对TauO-GlcNAcylation的影响。我们报道，DHA治疗减轻了Barnes迷宫中海马CA1LTP和空间学习和记忆的缺陷，并减轻了hTau转基因小鼠的上下文恐惧条件测试。机械上,我们发现，DHA通过上调TauO-GlcNAcylation和减弱Tau过度磷酸化发挥了显着的保护作用。通过分子对接,我们发现DHA和O-GlcNAc转移酶（OGT）之间的稳定结合。我们进一步报道DHA处理对OGT的表达没有影响，但它促进了OGT核出口，从而增强OGT介导的TauO-GlcNAcylation。一起来看,这些结果表明，DHA通过促进OGT的细胞质易位和重建TauO-GlcNAcylation/磷酸化的平衡发挥神经保护作用，增强Tau的O-GlcNAcylation，这表明DHA可能是抗tau蛋白病的潜在治疗剂。
