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Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy
Journal of Alzheimer’s Disease ( IF 4 ) Pub Date : 2021-09-09 , DOI: 10.3233/jad-210643
Lei Xia 1, 2, 3 , Yayan Pang 1, 2, 3 , Junjie Li 1, 2, 3 , Bin Wu 1, 2, 3 , Yehong Du 1, 2, 3 , Yuxin Chen 1, 2, 3 , Man Luo 1, 2, 3 , Yan Wang 1, 2, 3 , Zhifang Dong 1, 2, 3
Affiliation  

Background:Tauopathies are a group of neurodegenerative disorders, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tau pathology. Hyperphosphorylation modification promotes tau protein misfolding and aggregation into neurofibrillary tangles, leading to impairments of synaptic plasticity and learning and memory. However, very limited therapeutic strategies are available. Objective:In the present study, we wanted to investigate the potential effects of Dihydroartemisinin (DHA) on tauopathies. Methods:We constructed adeno-associated virus carrying hTau cDNA (AAVhTau) to establish a mouse model of tauopathy through intrahippocampal microinjection. Using a combination of behavioral test, electrophysiological recording, and western blotting assay, we examined the neuroprotective effects of DHA on learning and memory deficits in mice with tauopathy. Results:DHA improved learning and memory and increased hippocampal CA1 long-term potentiation (LTP) in mice overexpressed human tau (hTau) in the hippocampus. More importantly, further study revealed that DHA could induce protein O-GlcNAcylation modification and reduce protein phosphorylation. O-GlcNAc transferase inhibitor alloxan could suppress DHA-induced protein O-GlcNAcylation, and subsequently prevent therapeutic effect of DHA on the deficits of learning and memory as well as synaptic plasticity in hTau mice. Conclusion:These results indicate that DHA may exert neuroprotective role in tauopathy through a crosstalk between O-GlcNAcylation and phosphorylation, suggesting a potential therapeutic for learning and memory deficits associated with tau pathology.

中文翻译:

双氢青蒿素在 Tau 蛋白病变小鼠模型中诱导 O-GlcNAcylation 并改善认知功能

背景:Tauopathies 是一组神经退行性疾病,包括阿尔茨海默病 (AD) 和具有 tau 病理学的额颞叶变性。过度磷酸化修饰促进 tau 蛋白错误折叠和聚集成神经原纤维缠结,导致突触可塑性和学习记忆受损。然而,可用的治疗策略非常有限。目的:在本研究中,我们想研究双氢青蒿素 (DHA) 对 tauopathies 的潜在影响。方法:我们构建了携带hTau cDNA的腺相关病毒(AAVhTau),通过海马内显微注射建立tau蛋白病小鼠模型。结合行为测试、电生理记录和蛋白质印迹分析,我们检查了 DHA 对 tau 蛋白病小鼠学习和记忆缺陷的神经保护作用。结果:在海马中过表达人 tau (hTau) 的小鼠中,DHA 改善了学习和记忆并增加了海马 CA1 长时程增强 (LTP)。更重要的是,进一步的研究表明,DHA 可以诱导蛋白质 O-GlcNAcylation 修饰并降低蛋白质磷酸化。O-GlcNAc 转移酶抑制剂四氧嘧啶可以抑制 DHA 诱导的蛋白质 O-GlcNAcylation,随后阻止 DHA 对 hTau 小鼠学习记忆和突触可塑性缺陷的治疗作用。结论:这些结果表明 DHA 可能通过 O-GlcNAcylation 和磷酸化之间的相互作用在 tau 蛋白病中发挥神经保护作用,
更新日期:2021-09-12
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