Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis.
Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis.
复制标题
DOI：
10.1016/j.bbi.2020.03.004
复制
发表时间：
2020-07
期刊：
影响因子：
--
通讯作者：
Gelbard HA
中科院分区：
文献类型：
--
作者：
Hammond JW;Bellizzi MJ;Ware C;Qiu WQ;Saminathan P;Li H;Luo S;Ma SA;Li Y;Gelbard HA
多发性硬化症（MS）是一种以灰质和白色物质损伤为特征的CNS炎性神经退行性疾病。小胶质细胞活化和突触密度降低是灰质病理学的关键特征，其可以用MOG 35 -55实验性自身免疫性脑脊髓炎（EAE）建模。在正常发育和疾病中，补体沉积与小胶质细胞吞噬相结合已被证明是修剪突触的机制。我们使用C1 qa和C3基因敲除小鼠测试了EAE海马中是否有过量的补体产生，以及补体依赖性突触丢失是否是EAE变性的来源。我们发现C1 q和C3蛋白和mRNA水平在EAE小鼠中升高。C3基因的丢失保护小鼠免于EAE诱导的突触丢失，减少小胶质细胞活化，降低EAE临床评分的严重程度，并保护背景恐惧条件反射后的记忆/冻结行为。与WT EAE小鼠相比，患有EAE的C1 qa KO小鼠的这些测量值几乎没有变化。因此，病理表达和激活的早期补体途径，特别是在C3的水平，有助于海马灰质病理在EAE。
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.
登录
查看更多内容
影响因子：
7.3
作者：
da Costa, Mariana Gaya;Poppelaars, Felix;Seelen, Marc A.
通讯作者：
Seelen, Marc A.
影响因子：
6.2
作者：
Boos, LA;Szalai, AJ;Barnum, SR
通讯作者：
Barnum, SR
影响因子：
3.6
作者：
Hu, Xianzhen;Holers, V. Michael;Barnum, Scott R.
通讯作者：
Barnum, Scott R.
影响因子：
6
作者：
Bullard, Daniel C.;Hu, Xianzhen;Barnum, Scott R.
通讯作者：
Barnum, Scott R.
影响因子：
4.4
作者：
Bullard, DC;Hu, XZ;Barnum, SR
通讯作者：
Barnum, SR