An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease.
An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease.
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环氧化物水解酶抑制剂减少阿尔茨海默病小鼠模型中的神经炎症。
DOI：
10.1126/scitranslmed.abb1206
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发表时间：
2020-12-09
影响因子：
17.1
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Ghosh A;Comerota MM;Wan D;Chen F;Propson NE;Hwang SH;Hammock BD;Zheng H
神经炎症在阿尔茨海默病（AD）中的作用越来越受到重视。环氧脂肪酸（EpFA）是花生四烯酸代谢途径的衍生物，具有抗炎活性。然而，由于它们被可溶性环氧化物水解酶（sEH）快速水解，它们的功效是有限的。我们报道sEH主要在星形胶质细胞中表达，并且其浓度在AD患者的死后脑组织和AD的5xFAD β-淀粉样蛋白小鼠模型中升高。AD小鼠脑中表达的sEH的量与脑EpFA浓度的降低相关。使用特定的小分子sEH抑制剂，1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲（TPPU），我们报告说，TPPU治疗保护AD小鼠对LPS诱导的炎症在体内。通过饮用水对5xFAD小鼠模型长期给予TPPU逆转了小胶质细胞和星形胶质细胞反应性以及免疫途径失调。这与减少的β-淀粉样蛋白病理学和改善的突触完整性和两项行为测试的认知功能有关。重要的是，TPPU治疗与5xFAD小鼠脑中EpFA浓度的增加相关，证明了脑渗透和靶点接合。这些发现支持进一步研究TPPU作为治疗AD的潜在治疗剂。用生物可利用的小分子抑制剂阻断环氧化物水解酶减少阿尔茨海默病小鼠模型中的神经病理学。神经炎症与阿尔茨海默病（AD）密切相关。由花生四烯酸产生的环氧脂质具有抗炎特性，但它们被可溶性环氧化物水解酶（sEH）迅速转化。我们发现sEH在AD患者和淀粉样蛋白小鼠模型的脑中升高，这表明阻断sEH可以补充环氧脂质并对抗神经炎症。事实上，用小分子sEH抑制剂治疗淀粉样蛋白小鼠恢复了环氧脂质，减少了神经炎症和淀粉样蛋白病理学，并改善了认知能力。我们的研究确定了调节神经炎症的脂质代谢途径，并为sEH抑制剂作为AD治疗提供了支持。
Neuroinflammation has been increasingly recognized to play a critical role in Alzheimer’s disease (AD). The epoxy fatty acids (EpFAs) are derivatives of the arachidonic acid metabolism pathway and have anti-inflammatory activities. However, their efficacy is limited due to their rapid hydrolysis by the soluble epoxide hydrolase (sEH). We report that sEH is predominantly expressed in astrocytes and its concentrations are elevated in postmortem brain tissue from AD patients and in the 5xFAD β-amyloid mouse model of AD. The amount of sEH expressed in AD mouse brains correlated with a reduction in brain EpFA concentrations. Using a specific small molecule sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), we report that TPPU treatment protected AD mice against LPS-induced inflammation in vivo. Long-term administration of TPPU to the 5xFAD mouse model via drinking water reversed microglia and astrocyte reactivity and immune pathway dysregulation. This was associated with reduced β-amyloid pathology and improved synaptic integrity and cognitive function on two behavioral tests. Importantly, TPPU treatment correlated with an increase in EpFA concentrations in the brains of 5xFAD mice, demonstrating brain penetration and target engagement. These findings support further investigation of TPPU as a potential therapeutic agent for the treatment of AD. Blocking epoxide hydrolase with a bioavailable small molecule inhibitor reduces neuropathology in an Alzheimer’s disease mouse model. Neuroinflammation is strongly implicated in Alzheimer’s disease (AD). The epoxy lipids produced from arachidonic acid have anti-inflammatory properties, but they are rapidly turned over by the soluble epoxide hydrolase (sEH). We found that sEH is elevated in the brain of AD patients and an amyloid mouse model, suggesting that blocking sEH may replenish the epoxy lipids and combat neuroinflammation. Indeed, treating the amyloid mice with a small molecule sEH inhibitor restored the epoxy lipids, reduced neuroinflammation and amyloid pathology, and improved cognition. Our study identifies a lipid metabolic pathway regulating neuroinflammation and provides support for sEH inhibitors as AD therapy.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Bystrom J;Wray JA;Sugden MC;Holness MJ;Swales KE;Warner TD;Edin ML;Zeldin DC;Gilroy DW;Bishop-Bailey D
通讯作者：
Bishop-Bailey D
影响因子：
17.1
作者：
Ghosh, Anamitra;Tyson, Trevor;Brundin, Patrik
通讯作者：
Brundin, Patrik
影响因子：
3.5
作者：
Harris TR;Hammock BD
通讯作者：
Hammock BD