The activation of inflammatory responses in the brain is potentiated by over-expressing acetylcholinesterase in myeloid lineage of transgenic mice.

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yingjie Xia, Xiaoyang Wang, Maggie Suisui Guo, Jiahui Wu, Jin Gao, Tina T X Dong, Karl W K Tsim
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引用次数: 0

Abstract

Acetylcholinesterase (AChE) has functions in neuroinflammation, beyond its classical role in neurotransmission. Understanding the role of AChE in neuroinflammation is of great significance, as it highlights the potential therapeutic targets for the treatment of neurodegenerative diseases. In an in vitro study, the expression of AChE was up-regulated in lipopolysaccharide (LPS)-induced microglia/macrophage and contrarily potentiated the inflammatory responses via disturbing the cholinergic anti-inflammatory pathway (CAP). However, the regulation of AChE in neuroinflammation has not been revealed in vivo yet. Here, we aim to uncover the inflammatory roles of microglial AChE in LPS-induced neuroinflammation by using the conditional AChE over-expression mouse model. AChE was specifically over-expressed in the myeloid cell linkage of mouse by applying CRISPR/cas9 combined with Cre-LoxP system. LPS was intraperitoneally injected into the mice to induce inflammation. The results showed that the inflammation, induced by LPS, was aggravated in the brain of transgenic mice having over-expression of AChE in microglia. The expressions of pro-inflammatory cytokines were robustly up-regulated in the brains of LPS-treated transgenic mice, as compared to the LPS-treated wildtypes. In parallel, the activations of microglia and astrocytes in hippocampus were enhanced significantly in AChE transgenic mice. Transcriptomics analysis further confirmed the severer inflammation in the transgenic mice than the wildtype after LPS administration. These findings shed light on the regulation of microglial AChE in neuroinflammation in vivo for the first time, presenting another angle to understand the role of AChE in neurodegenerative diseases.

在转基因小鼠的髓系中过度表达乙酰胆碱酯酶,可增强大脑炎症反应的激活作用。
乙酰胆碱酯酶(AChE)除了在神经传导中发挥传统作用外,还在神经炎症中发挥作用。了解乙酰胆碱酯酶在神经炎症中的作用意义重大,因为它凸显了治疗神经退行性疾病的潜在治疗靶点。在一项体外研究中,AChE 在脂多糖(LPS)诱导的小胶质细胞/巨噬细胞中表达上调,并通过干扰胆碱能抗炎途径(CAP)增强炎症反应。然而,AChE 在神经炎症中的调控尚未在体内得到揭示。在这里,我们利用条件性 AChE 过度表达小鼠模型,旨在揭示小胶质细胞 AChE 在 LPS 诱导的神经炎症中的炎症作用。通过CRISPR/cas9结合Cre-LoxP系统,AChE被特异性地过度表达在小鼠的髓系细胞连接中。小鼠腹腔注射 LPS 诱导炎症。结果表明,在小胶质细胞中 AChE 过度表达的转基因小鼠脑内,LPS 诱导的炎症加剧。与经 LPS 处理的野生型小鼠相比,经 LPS 处理的转基因小鼠脑内促炎细胞因子的表达明显上调。与此同时,AChE 转基因小鼠海马中的小胶质细胞和星形胶质细胞的活化也显著增强。转录组学分析进一步证实,在给予 LPS 后,转基因小鼠的炎症比野生型严重。这些发现首次揭示了小胶质细胞 AChE 在体内神经炎症中的调控作用,为了解 AChE 在神经退行性疾病中的作用提供了另一个角度。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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