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

Inhibition of Soluble Epoxide Hydrolase Confers Neuroprotection and Restores Microglial Homeostasis in a Tauopathy Mouse Model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Inhibition of Soluble Epoxide Hydrolase Confers Neuroprotection and Restores Microglial Homeostasis in a Tauopathy Mouse Model Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6038641/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Apr, 2025 Read the published version in Molecular Neurodegeneration → Version 1 posted 5 You are reading this latest preprint version 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 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. Alzheimer’s disease epoxyeicosatrienoic acids microglia neurodegeneration soluble epoxide hydrolase tau Full Text Supplementary Files Wangetal.SupplementalMaterials.pdf Cite Share Download PDF Status: Published Journal Publication published 23 Apr, 2025 Read the published version in Molecular Neurodegeneration → Version 1 posted Editorial decision: Minor revision 30 Mar, 2025 Reviewers agreed at journal 19 Feb, 2025 Reviewers invited by journal 19 Feb, 2025 Editor assigned by journal 17 Feb, 2025 First submitted to journal 15 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6038641","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":418178474,"identity":"a7d4cdc5-9cff-468a-9c2c-dcef2c8b6f86","order_by":0,"name":"Shuo Wang","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shuo","middleName":"","lastName":"Wang","suffix":""},{"id":418178475,"identity":"ca242f33-57ba-4795-a82d-921ce7baaae6","order_by":1,"name":"Chuangye Qi","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chuangye","middleName":"","lastName":"Qi","suffix":""},{"id":418178476,"identity":"9e27da1d-a1fc-4e0b-a28d-a7f308afbe91","order_by":2,"name":"Chetan Rajpurohit","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Chetan","middleName":"","lastName":"Rajpurohit","suffix":""},{"id":418178477,"identity":"010b4c69-de3c-46f8-852e-51b4bb2b5f10","order_by":3,"name":"Baijayanti Ghosh","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Baijayanti","middleName":"","lastName":"Ghosh","suffix":""},{"id":418178478,"identity":"665f0789-fe3a-4088-a09f-63032c008194","order_by":4,"name":"Wen Xiong","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Xiong","suffix":""},{"id":418178479,"identity":"0a739e66-806b-4f9e-8f34-9a53e39c4a1e","order_by":5,"name":"Baiping Wang","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Baiping","middleName":"","lastName":"Wang","suffix":""},{"id":418178480,"identity":"c0b3fb67-5e6a-49d8-8e5d-7ab233bde9d1","order_by":6,"name":"Yanyan Qi","email":"","orcid":"","institution":"Baylor College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yanyan","middleName":"","lastName":"Qi","suffix":""},{"id":418178481,"identity":"1a33508f-67d4-448d-a1fd-693a32e695d2","order_by":7,"name":"Sun Hee Hwang","email":"","orcid":"","institution":"University of California Davis","correspondingAuthor":false,"prefix":"","firstName":"Sun","middleName":"Hee","lastName":"Hwang","suffix":""},{"id":418178482,"identity":"033a2239-f6ca-4cdc-aa16-8893aed8cfe2","order_by":8,"name":"Bruce D. 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However, their efficacy is limited due to the rapid hydrolysis\u0026nbsp;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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: 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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: These findings demonstrate that sEH blockade or EET augmentation confer therapeutic benefit against neurodegenerative tauopathies through parallel targeting of neuronal and microglial pathways.\u003c/p\u003e","manuscriptTitle":"Inhibition of Soluble Epoxide Hydrolase Confers Neuroprotection and Restores Microglial Homeostasis in a Tauopathy Mouse Model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-24 06:01:17","doi":"10.21203/rs.3.rs-6038641/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-03-30T22:53:18+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-02-19T21:41:11+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-02-19T18:15:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-17T13:28:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Molecular Neurodegeneration","date":"2025-02-15T18:14:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"molecular-neurodegeneration","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mond","sideBox":"Learn more about [Molecular Neurodegeneration](http://molecularneurodegeneration.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mond/default.aspx","title":"Molecular Neurodegeneration","twitterHandle":"@MolNeuro","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"16c48fe4-3d65-4e9a-b387-4f88af175925","owner":[],"postedDate":"February 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-28T16:02:51+00:00","versionOfRecord":{"articleIdentity":"rs-6038641","link":"https://doi.org/10.1186/s13024-025-00844-x","journal":{"identity":"molecular-neurodegeneration","isVorOnly":false,"title":"Molecular Neurodegeneration"},"publishedOn":"2025-04-23 15:57:56","publishedOnDateReadable":"April 23rd, 2025"},"versionCreatedAt":"2025-02-24 06:01:17","video":"","vorDoi":"10.1186/s13024-025-00844-x","vorDoiUrl":"https://doi.org/10.1186/s13024-025-00844-x","workflowStages":[]},"version":"v1","identity":"rs-6038641","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6038641","identity":"rs-6038641","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}