Shie Feng-Shiun, Montine Kathleen S, Breyer Richard M, Montine Thomas J
Department of Pathology, University of Washington, Seattle 98104, USA.
Brain Pathol. 2005 Apr;15(2):134-8. doi: 10.1111/j.1750-3639.2005.tb00509.x.
Epidemiologic and animal model data support a role for the prostaglandin pathway in AD pathogenesis. However, unexpected toxicity from protracted use of some nonsteroidal anti-inflammatory drugs (NSAIDs) compels investigation of therapeutic targets in this pathway other than COX inhibitors. Previously, we have shown that mice lacking one specific receptor for PGE2, EP2 (EP2-/-), are protected from the indirect neurotoxic effects of cerebral innate immune response mediated by CD14-dependent activation. Here we review data showing that EP2-/- microglia have a highly desirable combination of features: ablated indirect neurotoxicity following exposure to Abeta(1-42) coupled with enhanced phagocytosis of Abeta peptides, both synthetic and those deposited in human brain. These data point to microglial EP2 as a more focused target within the PG pathway for therapy in AD.
流行病学和动物模型数据支持前列腺素途径在阿尔茨海默病发病机制中发挥作用。然而,长期使用某些非甾体抗炎药(NSAIDs)产生的意外毒性促使人们研究该途径中除COX抑制剂以外的治疗靶点。此前,我们已经表明,缺乏前列腺素E2(PGE2)的一种特定受体EP2的小鼠(EP2基因敲除小鼠,即EP2-/-)可免受由CD14依赖性激活介导的脑先天性免疫反应的间接神经毒性作用。在此,我们回顾相关数据,这些数据表明EP2-/-小胶质细胞具有一系列非常理想的特征组合:暴露于β淀粉样蛋白(1-42)(Abeta(1-42))后间接神经毒性消失,同时对合成的以及沉积在人脑内的β淀粉样肽的吞噬作用增强。这些数据表明,小胶质细胞EP2是前列腺素途径中一个更具针对性的阿尔茨海默病治疗靶点。