Inhibition of Soluble Epoxide Hydrolase Confers Neuroprotection and Restores Microglial Homeostasis in a Tauopathy Mouse Model

Background: The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by the soluble epoxide hydrolase (sEH). Accordingly, inhibition of sEH has been shown to stabilize the EETs and dampen neuroinflammation in Ab mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway in other cell types of the CNS and in other neurodegenerative conditions are less understood. Methods: Here we examined the mechanisms and the functional role of the sEH-EET axis in tauopathy by treating the PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice, followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical characterization, and behavioral analysis. We also tested the effect of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons that develop seeding-induced Tau inclusions. Results: We show that sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglia reactivity. snRNA-seq revealed that TPPU treatment resulted in the upregulation of actin cytoskeleton and excitatory synaptic pathway genes. Treating the human iPSC-derived neurons with TPPU led to enhanced synaptic density without affecting Tau accumulation, indicating a cell-autonomous effect of sEH blockade in neuroprotection. Further, sEH inhibition reversed disease-associated and interferon-response microglia states in PS19 mice and EET supplementation enhanced Tau phagocytosis and clearance in primary microglia cultures. Conclusion: These findings demonstrate that sEH blockade or EET augmentation confer therapeutic benefit against neurodegenerative tauopathies through parallel targeting of neuronal and microglial pathways.