Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, Neurosciences Graduate Program, Stanford University, Stanford, California 94305, and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
J Neurosci. 2014 Apr 23;34(17):5882-94. doi: 10.1523/JNEUROSCI.0410-14.2014.
A persistent and nonresolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1ΔE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Aβ deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology.
对淀粉样蛋白肽积累的持续且未解决的炎症反应是阿尔茨海默病（AD）发展的主要特征。为了应对淀粉样蛋白肽的积累，小胶质细胞作为大脑的固有免疫细胞，会产生一种加速突触和神经元损伤的毒性炎症反应。许多促炎信号通路与神经退行性变的进展有关。然而，能够抑制淀粉样蛋白诱导的炎症的内源性抗炎途径代表了一个相对未被探索的领域。在这里，我们报告前列腺素 E2（PGE2）EP4 受体的信号传导能够强烈抑制小胶质细胞对淀粉样蛋白β 42 肽的炎症反应。在培养的小胶质细胞中，EP4 刺激可降低淀粉样蛋白β 42 诱导的炎症因子水平，并增强对淀粉样蛋白β 42 的吞噬作用。微阵列分析表明，EP4 刺激广泛拮抗小胶质细胞中淀粉样蛋白β 42 驱动的基因表达变化，富集了 IRF1、IRF7 和 NF-κB 转录因子的靶基因。在体内，APPSwe-PS1ΔE9（APP-PS1）小鼠中条件性敲除小胶质细胞的 EP4 会增加炎症基因表达、氧化蛋白修饰和大脑中的淀粉样蛋白β 沉积，在病理学的早期阶段，但在后期阶段不会增加，这表明小胶质细胞 EP4 信号在 APP-PS1 模型中的早期抗炎功能。最后，EP4 受体水平在从正常到 AD 状态的人脑皮质中显著降低，这表明在临床前 AD 发展过程中，这种有益的信号系统的早期丧失可能导致随后的病理进展。
