Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
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DOI：
10.1523/jneurosci.2117-15.2016
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发表时间：
2016-01-13
影响因子：
5.3
通讯作者：
Zheng, Hui
中科院分区：
文献类型：
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作者：
Lian, Hong;Litvinchuk, Alexandra;Zheng, Hui
越来越多的证据支持神经炎症在阿尔茨海默病（AD）发病机制中的作用。以前，我们确定了一个神经胶质细胞信号通路，其中A β作为星形胶质细胞核因子κ B（NE-κ B）的上游激活剂，导致补体C3的释放，其作用于神经元C3 a受体（C3 aR），影响树突状细胞形态和认知功能。在这里，我们报告，星形胶质细胞补体激活也调节A β动力学在体外和淀粉样病变的AD小鼠模型通过小胶质细胞C3 aR。我们发现，在原代小胶质细胞培养，急性C3或C3 a激活促进，而慢性C3/C3 a治疗减弱，小胶质细胞的吞噬作用，慢性C3暴露的效果可以通过与C3 aR拮抗剂和C3 aR基因缺失的共同治疗来阻断。我们进一步证明，淀粉样前体蛋白（APP）转基因小鼠的A β病理学和神经炎症因星形胶质细胞NE-κ B过度活化和导致的C3升高而恶化，而用C3 aR拮抗剂（C3 aRA）治疗可改善斑块负荷和小胶质细胞增生。我们的研究定义了一种补体依赖性细胞间串扰，其中神经元过度产生A β激活星形胶质细胞NE-κ B，引发C3的细胞外释放。这促进了致病循环，通过该致病循环，C3又与神经元和小胶质细胞C3 aR相互作用以改变认知功能并损害A β吞噬作用。这种前馈环可以通过C3 aR抑制有效地阻断，支持C3 aR拮抗剂在慢性神经炎症条件下的治疗潜力。
Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron glia signaling pathway whereby A beta acts as an upstream activator of astroglial nuclear factor kappa B (NE-kappa B), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates A beta dynamics in vitro and amylo id pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion of C3aR. We further demonstrate that A beta pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NE-kappa B hyperactivat ion and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of A beta activates astroglial NE-kappa B to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair A beta phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuro inflammation conditions.