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Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis
Brain, Behavior, and Immunity ( IF 8.8 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.bbi.2020.03.004
Jennetta W Hammond 1 , Matthew J Bellizzi 2 , Caroline Ware 1 , Wen Q Qiu 1 , Priyanka Saminathan 3 , Herman Li 1 , Shaopeiwen Luo 1 , Stefanie A Ma 1 , Yuanhao Li 1 , Harris A Gelbard 4
Affiliation  

Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease of the CNS characterized by both grey and white matter injury. Microglial activation and a reduction in synaptic density are key features of grey matter pathology that can be modeled with MOG35-55 experimental autoimmune encephalomyelitis (EAE). Complement deposition combined with microglial engulfment has been shown during normal development and in disease as a mechanism for pruning synapses. We tested whether there is excess complement production in the EAE hippocampus and whether complement-dependent synapse loss is a source of degeneration in EAE using C1qa and C3 knockout mice. We found that C1q and C3 protein and mRNA levels were elevated in EAE mice. Genetic loss of C3 protected mice from EAE-induced synapse loss, reduced microglial activation, decreased the severity of the EAE clinical score, and protected memory/freezing behavior after contextual fear conditioning. C1qa KO mice with EAE showed little to no change on these measurements compared to WT EAE mice. Thus, pathologic expression and activation of the early complement pathway, specifically at the level of C3, contributes to hippocampal grey matter pathology in the EAE.

中文翻译:

多发性硬化症小鼠模型中补体依赖性突触丢失和小胶质细胞增生

多发性硬化症 (MS) 是一种以灰质和白质损伤为特征的中枢神经系统炎症性神经退行性疾病。小胶质细胞激活和突触密度降低是灰质病理学的关键特征,可以用 MOG35-55 实验性自身免疫性脑脊髓炎 (EAE) 建模。补体沉积结合小胶质细胞吞噬已在正常发育和疾病中显示为修剪突触的机制。我们使用 C1qa 和 C3 敲除小鼠测试了 EAE 海马中是否存在过量补体产生,以及补体依赖性突触丢失是否是 EAE 退化的来源。我们发现 EAE 小鼠的 C1q 和 C3 蛋白和 mRNA 水平升高。C3 的遗传损失保护小鼠免受 EAE 诱导的突触损失,减少小胶质细胞激活,降低了 EAE 临床评分的严重程度,并在情境恐惧条件反射后保护了记忆/冻结行为。与 WT EAE 小鼠相比,具有 EAE 的 C1qa KO 小鼠在这些测量值上几乎没有变化。因此,早期补体通路的病理表达和激活,特别是在 C3 水平,有助于 EAE 中的海马灰质病理。
更新日期:2020-07-01
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