The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer’s disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.

酶溶性环氧化物水解酶 (sEH) 的抑制作用已在几种外周炎症相关疾病中显示出临床治疗效果，其中 3 种化合物已在临床试验中。然而，这种酶在神经炎症过程中的作用在很大程度上被忽视了。在此，我们公开了 sEH 作为治疗阿尔茨海默病 (AD) 的新靶点的药理学验证。使用 3 种结构不同且有效的 sEH 抑制剂作为化学探针，在 2 种与年龄相关的认知衰退和 AD 模型中使用了认知障碍和病理标志的评估。sEH 在 AD 患者的大脑中上调。我们的研究结果支持中枢 sEH 抑制的有益作用，包括减少认知障碍、神经炎症、tau 过度磷酸化病理、以及淀粉样斑块的数量。这项研究表明，通过靶向 sEH 抑制大脑炎症是 AD 的相关治疗策略。