Lei Xia , Junjie Li , Yayan Pang , Mingliang Xu , Yehong Du , Mulan Chen , Boqing Xu , Yiqiong Qiu , Zhifang Dong
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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.</p></div>","PeriodicalId":54549,"journal":{"name":"Progress in Neuro-Psychopharmacology & Biological Psychiatry","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice\",\"authors\":\"Lei Xia , Junjie Li , Yayan Pang , Mingliang Xu , Yehong Du , Mulan Chen , Boqing Xu , Yiqiong Qiu , Zhifang Dong\",\"doi\":\"10.1016/j.pnpbp.2024.111105\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). 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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. 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引用次数: 0
摘要
Tau病是多种神经退行性疾病的统称,其特征是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-连锁-N-乙酰葡萄糖氨酰化(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是否能通过特异性促进Tau O-GlcNAcylation来改善hTau转基因小鼠的突触和认知功能仍不清楚。在这里,我们引入了hTau转基因小鼠--一种更理想的tau病模型--来研究DHA对Tau O-GlcNAcylation的影响。我们发现,DHA能缓解hTau转基因小鼠海马CA1 LTP的缺陷,以及在巴恩斯迷宫和情境恐惧条件反射测试中的空间学习和记忆缺陷。从机理上讲,我们发现 DHA 通过上调 Tau O-GlcNAcylation 和减轻 Tau 过度磷酸化发挥了显著的保护作用。通过分子对接,我们发现 DHA 与 O-GlcNAc 转移酶(OGT)之间存在稳定的结合。我们还进一步发现,DHA处理对OGT的表达没有影响,但它促进了OGT的核输出,从而增强了OGT介导的Tau O-GlcNAcylation。综上所述,这些结果表明,DHA通过促进OGT的胞质转运,重建Tau O-GlcNAcylation/磷酸化的平衡,增强Tau的O-GlcNAcylation,从而发挥神经保护作用,提示DHA可能是一种潜在的治疗tauopathy的药物。
Dihydroartemisinin promotes tau O-GlcNAcylation and improves cognitive function in hTau transgenic mice
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.
期刊介绍:
Progress in Neuro-Psychopharmacology & Biological Psychiatry is an international and multidisciplinary journal which aims to ensure the rapid publication of authoritative reviews and research papers dealing with experimental and clinical aspects of neuro-psychopharmacology and biological psychiatry. Issues of the journal are regularly devoted wholly in or in part to a topical subject.
Progress in Neuro-Psychopharmacology & Biological Psychiatry does not publish work on the actions of biological extracts unless the pharmacological active molecular substrate and/or specific receptor binding properties of the extract compounds are elucidated.