Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models
Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models
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DOI：
10.1172/jci77487
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发表时间：
2015-01-01
影响因子：
15.9
通讯作者：
Andreasson, Katrin I.
中科院分区：
文献类型：
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作者：
Johansson, Jenny U.;Woodling, Nathaniel S.;Andreasson, Katrin I.
小胶质细胞是中枢神经系统的先天免疫细胞，执行维持正常神经功能的关键炎症和非炎症功能。例如，小胶质细胞清除错误折叠的蛋白质，精心设计营养因子，并调节和终止毒性炎症。然而，在阿尔茨海默病 (AD) 中，有益的小胶质细胞功能受损，加速突触和神经元损失。更好地了解导致小胶质细胞功能障碍的分子机制是确定延缓 AD 进展的潜在策略的重要目标。在人类流行病学研究和 AD 转基因啮齿动物模型中，炎性环氧合酶/前列腺素 E2 (COX/PGE(2)) 通路与临床前 AD 的发展有关。在这里，我们评估了重现小胶质细胞对 AID 肽反应的小鼠模型，并确定小胶质细胞特异性删除编码 PGE(2) 受体 EP2 的基因可恢复小胶质细胞趋化性和 Aβ 清除，抑制毒性炎症，增加细胞保护性胰岛素样生长因子 1 (IGF1) 信号传导，并防止突触损伤和记忆缺陷。我们的研究结果表明，EP2 信号传导抑制了 AD 发展过程中受损的有益小胶质细胞功能，并表明抑制 COX/PGE(2)/EP2 免疫途径有可能作为恢复健康小胶质细胞功能和预防 AD 进展的策略。
Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE(2)) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to AID peptides and determined that microglia-specific deletion of the gene encoding the PGE(2) receptor EP2 restores microglial chemotaxis and A beta clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE(2)/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.