BACKGROUND Soluble epoxide hydrolase (sEH) is a bifunctional enzyme with COOH-terminal hydrolase and NH2-terminal lipid phosphatase activities. It is expressed in various cell types in the brain and is involved in the pathogenesis of inflammatory and neurodegenerative diseases. Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disease. However, the pathological significance of sEH and underlying molecular mechanism in AD remain unclear. METHODS To examine the role of sEH in pathogenesis of AD, we used wild-type (WT) mice, soluble epoxide hydrolase deficient (sEH-/-) and two mouse models of AD, including amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (APP/PS1 Tg) and APP/PS1 Tg/sEH-/- mice. Western blotting analysis and immunohistochemistry assay were performed to evaluate the protein expression. Locomotion, nesting building ability, Y-maze, and Morris water maze tests were conducted to study mouse behavior. The levels of interleukin (IL)-1β, IL-4, IL-6, and IL-10 and the activities of NF-κB and nuclear factor of activated T cells (NFAT) were measured by commercial assay kits. The quantitative protein level profiling in the brain lysate was analyzed using LC-MS/MS approaches. RESULTS We demonstrated that the level of sEH was increased in the brain and predominantly appeared in hippocampal astrocytes of APP/PS1 Tg mice. Genetic ablation of sEH in APP/PS1 Tg mice delayed the progression of AD as evidenced by the alleviation in behavior outcomes and Aβ plaque deposition. In addition, loss of the function of sEH in APP/PS1 Tg mice increased astrogliosis and the production of astrocyte-derived anti-inflammatory cytokines including IL-1β, IL-4, and IL-10, as well as the activity of NF-kB and NFAT. Moreover, analysis of gene ontology in the AD brain revealed that important signaling pathways and processes related to AD pathogenesis such as translational regulation, oxidative stress, cytoskeleton reorganization, and small GTPase signal transduction were altered in APP/PS1 Tg/sEH-/- mice compared with APP/PS1 Tg mice. CONCLUSION Our results suggest that sEH is a crucial regulator in the progression of AD and might be a potential therapeutic target for the treatment of AD.

中文翻译：

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可溶性环氧化物水解酶的基因缺失延迟了阿尔茨海默氏病的进展。

背景技术可溶性环氧化物水解酶（sEH）是具有COOH末端水解酶和NH 2末端脂质磷酸酶活性的双功能酶。它在脑中以各种细胞类型表达，并参与炎性和神经退行性疾病的发病机理。阿尔茨海默氏病（AD）是一种进行性神经炎症和神经退行性疾病。然而，尚不清楚sEH的病理学意义及其在AD中的潜在分子机制。方法为了研究sEH在AD发病机理中的作用，我们使用了野生型（WT）小鼠，可溶性环氧化物水解酶缺陷（sEH-/-）和两种AD小鼠模型，包括淀粉样蛋白前体蛋白（APP）/早老蛋白1（ PS1）转基因（APP / PS1 Tg）和APP / PS1 Tg / sEH-/-小鼠。进行蛋白质印迹分析和免疫组织化学测定以评估蛋白质表达。运动，筑巢能力，Y迷宫和莫里斯水迷宫测试进行了研究鼠标行为。用商业化验试剂盒测量白介素（IL）-1β，IL-4，IL-6和IL-10的水平以及NF-κB的活性和活化T细胞（NFAT）的核因子。使用LC-MS / MS方法分析了脑裂解物中的定量蛋白质水平分析。结果我们证明sEH水平在脑中增加，并且主要出现在APP / PS1 Tg小鼠的海马星形胶质细胞中。APP / PS1 Tg小鼠中sEH的基因消融延迟了行为发展和Aβ斑块沉积的缓解，证明了AD的进展。此外，APP / PS1 Tg小鼠中sEH功能的丧失会增加星形胶质细胞增多症和星形胶质细胞源性抗炎细胞因子（包括IL-1β，IL-4，IL-10，以及NF-kB和NFAT的活性。此外，对AD大脑中的基因本体的分析表明，APP / PS1 Tg / sEH-/-小鼠改变了与AD发病相关的重要信号传导途径和过程，如翻译调控，氧化应激，细胞骨架重组和小GTPase信号转导。与APP / PS1 Tg小鼠相比。结论我们的结果表明sEH是AD进展中的关键调节因子，可能是AD治疗的潜在治疗靶标。与APP / PS1 Tg小鼠相比，APP / PS1 Tg / sEH-/-小鼠的GTPase和小GTPase信号转导发生了改变。结论我们的结果表明sEH是AD进展中的关键调节因子，可能是AD治疗的潜在治疗靶标。与APP / PS1 Tg小鼠相比，APP / PS1 Tg / sEH-/-小鼠的GTPase和小GTPase信号转导发生了改变。结论我们的结果表明sEH是AD进展中的关键调节因子，可能是AD治疗的潜在治疗靶标。