Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy.
Dihydroartemisinin Induces O-GlcNAcylation and Improves Cognitive Function in a Mouse Model of Tauopathy.
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DOI：
10.3233/jad-210643
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发表时间：
2021-09
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通讯作者：
Lei Xia;Yayan Pang;Junjie Li;Bin Wu;Ye-hong Du;Yuxin Chen;Man Luo;Yan Wang;Zhifang Dong
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作者：
Lei Xia;Yayan Pang;Junjie Li;Bin Wu;Ye-hong Du;Yuxin Chen;Man Luo;Yan Wang;Zhifang Dong
tau病是一组神经退行性疾病，包括阿尔茨海默病（AD）和额颞叶变性与tau病理。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。目的探讨双氢青蒿素（DHA）对牛头病的潜在作用。方法构建携带hTau cDNA的腺相关病毒（AAVhTau），通过海马内显微注射建立小鼠tau病模型。采用行为测试、电生理记录和免疫印迹分析相结合的方法，我们研究了DHA对牛头病小鼠学习和记忆缺陷的神经保护作用。结果DHA可改善小鼠海马过度表达人tau蛋白（hTau）的学习和记忆，增加海马CA1长期增强（LTP）。更重要的是，进一步的研究发现DHA可以诱导蛋白o - glcnac酰化修饰，降低蛋白磷酸化。O-GlcNAc转移酶抑制剂四氧嘧啶可以抑制DHA诱导的O-GlcNAc蛋白酰化，从而抑制DHA对hTau小鼠学习记忆缺陷和突触可塑性的治疗作用。结论DHA可能通过o - glcn酰化和磷酸化之间的相互作用在tau病中发挥神经保护作用，提示其具有治疗tau病理相关的学习和记忆缺陷的潜在作用。
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.