Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model
Abstract 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 soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-025-00844-x |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850139441291591680 |
|---|---|
| author | Shuo Wang Chuangye Qi Chetan Rajpurohit Baijayanti Ghosh Wen Xiong Baiping Wang Yanyan Qi Sung Hee Hwang Bruce D. Hammock Hongjie Li Li Gan Hui Zheng |
| author_facet | Shuo Wang Chuangye Qi Chetan Rajpurohit Baijayanti Ghosh Wen Xiong Baiping Wang Yanyan Qi Sung Hee Hwang Bruce D. Hammock Hongjie Li Li Gan Hui Zheng |
| author_sort | Shuo Wang |
| collection | DOAJ |
| description | Abstract 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 soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood. Methods Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions. Results sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures. Conclusion These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways. |
| format | Article |
| id | doaj-art-443a89ec94934ea5ab3f6757f581baf8 |
| institution | OA Journals |
| issn | 1750-1326 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj-art-443a89ec94934ea5ab3f6757f581baf82025-08-20T02:30:18ZengBMCMolecular Neurodegeneration1750-13262025-04-0120111910.1186/s13024-025-00844-xInhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse modelShuo Wang0Chuangye Qi1Chetan Rajpurohit2Baijayanti Ghosh3Wen Xiong4Baiping Wang5Yanyan Qi6Sung Hee Hwang7Bruce D. Hammock8Hongjie Li9Li Gan10Hui Zheng11Huffington Center on Aging, Baylor College of MedicineHuffington Center on Aging, Baylor College of MedicineHuffington Center on Aging, Baylor College of MedicineHuffington Center on Aging, Baylor College of MedicineHuffington Center on Aging, Baylor College of MedicineHuffington Center on Aging, Baylor College of MedicineHuffington Center on Aging, Baylor College of MedicineDepartment of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of CaliforniaDepartment of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of CaliforniaHuffington Center on Aging, Baylor College of MedicineHelen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell MedicineHuffington Center on Aging, Baylor College of MedicineAbstract 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 soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway in other CNS cell types and neurodegenerative conditions are less understood. Methods Here we investigated the mechanisms and functional role of the sEH-EET axis in tauopathy by treating PS19 mice with a small molecule sEH inhibitor TPPU and by crossing the PS19 mice with Ephx2 (gene encoding sEH) knockout mice. This was followed by single-nucleus RNA-sequencing (snRNA-seq), biochemical and immunohistochemical analysis, and behavioral assessments. Additionally, we examined the effects of the sEH-EET pathway in primary microglia cultures and human induced pluripotent stem cell (iPSC)-derived neurons exhibiting seeding-induced Tau inclusions. Results sEH inhibition improved cognitive function, rescued neuronal cell loss, and reduced Tau pathology and microglial reactivity. snRNA-seq revealed that TPPU treatment upregulated genes involved in actin cytoskeleton and excitatory synaptic pathways. Treatment of human iPSC-derived neurons with TPPU enhanced synaptic density without affecting Tau accumulation, suggesting a cell-autonomous neuroprotective effect of sEH blockade. Furthermore, sEH inhibition reversed disease-associated and interferon-responsive microglial states in PS19 mice, while EET supplementation promoted Tau phagocytosis and clearance in primary microglia cultures. Conclusion These findings demonstrate that sEH blockade or EET augmentation confers therapeutic benefit in neurodegenerative tauopathies by simultaneously targeting neuronal and microglial pathways.https://doi.org/10.1186/s13024-025-00844-xAlzheimer’s diseaseEpoxyeicosatrienoic acidsMicrogliaNeurodegenerationSoluble epoxide hydrolaseTau |
| spellingShingle | Shuo Wang Chuangye Qi Chetan Rajpurohit Baijayanti Ghosh Wen Xiong Baiping Wang Yanyan Qi Sung Hee Hwang Bruce D. Hammock Hongjie Li Li Gan Hui Zheng Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model Molecular Neurodegeneration Alzheimer’s disease Epoxyeicosatrienoic acids Microglia Neurodegeneration Soluble epoxide hydrolase Tau |
| title | Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model |
| title_full | Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model |
| title_fullStr | Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model |
| title_full_unstemmed | Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model |
| title_short | Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model |
| title_sort | inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model |
| topic | Alzheimer’s disease Epoxyeicosatrienoic acids Microglia Neurodegeneration Soluble epoxide hydrolase Tau |
| url | https://doi.org/10.1186/s13024-025-00844-x |
| work_keys_str_mv | AT shuowang inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT chuangyeqi inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT chetanrajpurohit inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT baijayantighosh inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT wenxiong inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT baipingwang inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT yanyanqi inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT sungheehwang inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT brucedhammock inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT hongjieli inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT ligan inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel AT huizheng inhibitionofsolubleepoxidehydrolaseconfersneuroprotectionandrestoresmicroglialhomeostasisinatauopathymousemodel |