Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression.
Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression.
复制标题
DOI：
10.1523/jneurosci.3932-10.2011
复制
发表时间：
2011-03-02
期刊：
影响因子：
--
通讯作者：
Tenner AJ
中科院分区：
文献类型：
--
作者：
Benoit ME;Tenner AJ
补体级联的激活是先天免疫系统的一种强大的效应机制，与神经炎症有关，但也与发育过程中不适当突触的消除有关。补体系统的识别成分C1 q的合成在脑缺血/再灌注和阿尔茨海默病（AD）时发生，表明C1 q可能是对损伤的反应。在体外，C1 q，在其他补体蛋白的情况下，提高神经元的活力和轴突生长，并防止Aβ诱导的神经元死亡，表明C1 q可能有直接的神经保护作用。在这里，研究这种体外神经保护作用的分子基础，向大鼠原代皮层神经元中加入C1 q显著上调与胆固醇代谢相关的基因（如CH 25 H和INSIG 2）的表达，并短暂降低神经元中的胆固醇水平，已知有助于神经突生长。此外，syntaxin-3的表达及其与SNAP 25的功能相关性增加。C1 q还增加了CREB和C/EBP-δ的核转位，这两种转录因子参与NGF表达并下调特定的miRNA，包括预测靶向（从而抑制）NGF和NT-3 mRNA的let-7 c。相应地，C1 q增加了NGF和NT-3的表达，并且siRNA抑制C/EBP-δ、NGF或NT-3的表达阻止了C1 q依赖的神经突生长。在C3 a或C5 a的存在下没有观察到这种神经保护作用。最后，诱导的神经元基因表达需要构象完整的C1 q。这些结果表明，C1 q可以直接促进神经元存活，从而证明免疫蛋白和神经元细胞之间的新的相互作用，可能有助于神经保护。
Activation of the complement cascade, a powerful effector mechanism of the innate immune system, is associated with neuroinflammation but also with elimination of inappropriate synapses during development. Synthesis of C1q, a recognition component of the complement system, occurs in brain upon ischemia/reperfusion and Alzheimer’s Disease (AD), suggesting that C1q may be a response to injury. In vitro, C1q, in the absence of other complement proteins, improves neuronal viability and neurite outgrowth and prevents Aβ-induced neuronal death suggesting that C1q may have a direct neuroprotective role. Here, investigating the molecular basis for this neuroprotection in vitro, addition of C1q to rat primary cortical neurons significantly up-regulated expression of genes associated with cholesterol metabolism, such as CH25H and INSIG2, and transiently decreased cholesterol levels in neurons, known to facilitate neurite outgrowth. In addition, the expression of syntaxin-3 and its functional association with SNAP25 was increased. C1q also increased the nuclear translocation of CREB and C/EBP-δ, two transcription factors involved in NGF expression and down-regulated specific miRNAs, including let-7c that is predicted to target (and thus inhibit) NGF and NT-3 mRNA. Accordingly, C1q increased expression of NGF and NT-3, and siRNA inhibition of C/EBP-δ, NGF or NT-3 expression prevented the C1q-dependent neurite outgrowth. No such neuroprotective effect is seen in the presence of C3a or C5a. Finally, the induced neuronal gene expression required conformationally intact C1q. These results show that C1q can directly promote neuronal survival thereby demonstrating new interactions between immune proteins and neuronal cells that may facilitate neuroprotection.