BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease, and its pathogenesis is closely associated with neuroinflammation. The control of neuroinflammation in AD is the focus of current research. soluble epoxide hydrolase (sEH) protein is increased in the brain tissues of patients with AD and has been targeted by multiple genome wide association studies as a prime target for treating AD. Since sEH induces nerve inflammation by degrading epoxyeicosatrienoic acids (EETs), application of sEH inhibitor and sEH gene knockout are effective ways to improve the bioavailability of EETs and inhibit or even resolve neuroinflammation in AD. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent sEH inhibitor that has been shown to be effective in preclinical animal models of a variety of chronic inflammatory diseases. This study aims to further explore whether TPPU can alleviate AD neuroinflammation. METHODS: We established an Aβ42-transgenic Drosophila melanogaster model using the galactose-regulated upstream promoter element 4 (GAL4) / upstream active sequence (UAS) expression system and investigated the protective and anti-neuroinflammatory effects of TPPU against Aβ toxicity. We detected behavioral indexes (survival time, crawling ability, and olfactory memory) and biochemical indexes malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in brain tissues of Aβ42 transgenic flies. Finally, we explored the anti-neuroinflammatory effect of TPPU and its possible mechanism by stimulating cocultures of human SH-SY5Y cells and HMC3 cells with Aβ(25-35) to model neuronal cell inflammation, and evaluated the cells by fluorescence microscopy, ELISA, Western Blot, and Real-time PCR. RESULTS: We found that TPPU improved the survival time, crawling ability, and olfactory memory of Aβ42-transgenic flies. We also observed reduction of MDA content and elevation of SOD activity in the brain tissues of these flies. In human cell models, we found that TPPU improved cell viability, reduced cell apoptosis, decreased lipid oxidation, inhibited oxidative damage, thus playing a neuroprotective role. The inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-18 (IL-18) were downregulated, and the mRNA expression of the M2 microglia markers CD206 and SOCS3 were upregulated by TPPU; thus, TPPU inhibited neuroinflammatory responses. TPPU exerted neuroprotective and anti-inflammatory effects by decreasing the protein expression of the sEH-encoding gene EPHX2 and increasing the levels of 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-epoxyeicosatrienoic acid (14,15-EET). The inhibitory effect of TPPU on Aβ(25-35)-mediated neuroinflammation was associated with inhibition of the toll like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) pathway and p38 mitogen activated protein kinases (MAPK)/NF-κB pathway. CONCLUSIONS: We report that the sEH inhibitor TPPU exerts neuroprotective and anti-neuroinflammatory effects in AD models, and it is expected that this drug could potentially be used for the prevention and treatment of AD.