Interaction of SLAMF8 and NINJ2 Promotes Neuroinflammation and Oxidative Stress by Activating the TLR4/NF-κB Pathway in Alzheimer’s Disease

Interaction of SLAMF8 and NINJ2 Promotes Neuroinflammation and Oxidative Stress by Activating the TLR4/NF-κB Pathway in Alzheimer’s Disease | 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 Article Interaction of SLAMF8 and NINJ2 Promotes Neuroinflammation and Oxidative Stress by Activating the TLR4/NF-κB Pathway in Alzheimer’s Disease Shuo Liu, Yuze He, He Chen, Wenwen Zhao, Heman Xu, Tao Bai, Juan Feng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5039115/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 May, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Aims: This study aimed to investigate the expression and role of Signaling Lymphocytic Activation Molecule Family Member 8 (SLAMF8) in Alzheimer’s disease (AD), particularly its interaction with NINJ2 in the TLR4/NF-κB signaling pathway. Methods: SLAMF8 expression levels in AD models were analyzed using the Gene Expression Omnibus (GEO) database. Validation of SLAMF8 expression was conducted through RT-PCR and Western blot in Aβ 1−42 -exposed SH-SY5Y cells, LPS-exposed HMC3 cells, and APP/PS1 transgenic mice. The interaction between SLAMF8 and NINJ2 was explored through co-immunoprecipitation, confocal immunofluorescence, and Western blot analyses, focusing on their roles in the TLR4/NF-κB signaling pathway. Results: SLAMF8 was significantly upregulated in AD models, and its overexpression activated the TLR4/NF-κB signaling pathway, leading to increased levels of pro-inflammatory cytokines and oxidative stress. NINJ2 was identified as a direct functional partner of SLAMF8, with co-localization observed in the cytoplasm. Knockout of NINJ2 abolished SLAMF8-mediated activation of the TLR4/NF-κB pathway, neuroinflammation, and oxidative stress. Conclusion: The SLAMF8-NINJ2-TLR4/NF-κB axis is a crucial signaling pathway in AD progression. SLAMF8 and NINJ2 emerge as potential therapeutic targets for managing AD, with significant implications for future research and clinical interventions. Biological sciences/Cell biology Biological sciences/Neuroscience Health sciences/Medical research Alzheimer’s disease (AD) SLAMF8 NINJ2 TLR4/NF-κB pathway neuroinflammation oxidative stress Therapeutic targets Full Text Additional Declarations No competing interests reported. Supplementary Files WB.docx Cite Share Download PDF Status: Published Journal Publication published 20 May, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 11 Nov, 2024 Reviewers agreed at journal 30 Oct, 2024 Reviews received at journal 28 Oct, 2024 Reviews received at journal 24 Oct, 2024 Reviewers agreed at journal 15 Oct, 2024 Reviewers agreed at journal 07 Oct, 2024 Reviewers invited by journal 05 Oct, 2024 Editor assigned by journal 05 Oct, 2024 Editor invited by journal 13 Sep, 2024 Submission checks completed at journal 12 Sep, 2024 First submitted to journal 05 Sep, 2024 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. 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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-5039115","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":376440856,"identity":"d1a3e288-0ab9-4ff7-af60-e23e1a34a59a","order_by":0,"name":"Shuo Liu","email":"","orcid":"","institution":"The Fourth People’s Hospital of Shenyang","correspondingAuthor":false,"prefix":"","firstName":"Shuo","middleName":"","lastName":"Liu","suffix":""},{"id":376440857,"identity":"a48d1f9e-d8da-4483-921b-363f7f630417","order_by":1,"name":"Yuze He","email":"","orcid":"","institution":"Shengjing Hospital of China Medical University, China Medical 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Disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer’s disease (AD), SLAMF8, NINJ2, TLR4/NF-κB pathway, neuroinflammation, oxidative stress, Therapeutic targets","lastPublishedDoi":"10.21203/rs.3.rs-5039115/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5039115/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAims:\u003c/h2\u003e \u003cp\u003eThis study aimed to investigate the expression and role of Signaling Lymphocytic Activation Molecule Family Member 8 (SLAMF8) in Alzheimer\u0026rsquo;s disease (AD), particularly its interaction with NINJ2 in the TLR4/NF-κB signaling pathway.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eSLAMF8 expression levels in AD models were analyzed using the Gene Expression Omnibus (GEO) database. Validation of SLAMF8 expression was conducted through RT-PCR and Western blot in Aβ\u003csub\u003e1\u0026minus;42\u003c/sub\u003e-exposed SH-SY5Y cells, LPS-exposed HMC3 cells, and APP/PS1 transgenic mice. The interaction between SLAMF8 and NINJ2 was explored through co-immunoprecipitation, confocal immunofluorescence, and Western blot analyses, focusing on their roles in the TLR4/NF-κB signaling pathway.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eSLAMF8 was significantly upregulated in AD models, and its overexpression activated the TLR4/NF-κB signaling pathway, leading to increased levels of pro-inflammatory cytokines and oxidative stress. NINJ2 was identified as a direct functional partner of SLAMF8, with co-localization observed in the cytoplasm. Knockout of NINJ2 abolished SLAMF8-mediated activation of the TLR4/NF-κB pathway, neuroinflammation, and oxidative stress.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThe SLAMF8-NINJ2-TLR4/NF-κB axis is a crucial signaling pathway in AD progression. SLAMF8 and NINJ2 emerge as potential therapeutic targets for managing AD, with significant implications for future research and clinical interventions.\u003c/p\u003e","manuscriptTitle":"Interaction of SLAMF8 and NINJ2 Promotes Neuroinflammation and Oxidative Stress by Activating the TLR4/NF-κB Pathway in Alzheimer’s Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-09 04:49:35","doi":"10.21203/rs.3.rs-5039115/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-11T05:46:37+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"321715157632557510255912600073646001450","date":"2024-10-30T11:38:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-28T17:29:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-24T12:59:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5252509555804879148702795035743861965","date":"2024-10-15T23:05:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"131075129558712388393483991096331980933","date":"2024-10-07T17:30:40+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-05T15:49:44+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-05T15:46:36+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-09-13T14:20:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-09-12T09:57:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-09-05T14:54:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f82415e4-06ea-46b6-93d2-ab1fe5fde455","owner":[],"postedDate":"December 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":40069209,"name":"Biological sciences/Cell biology"},{"id":40069210,"name":"Biological sciences/Neuroscience"},{"id":40069211,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-05-26T16:01:16+00:00","versionOfRecord":{"articleIdentity":"rs-5039115","link":"https://doi.org/10.1038/s41598-025-02097-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-05-20 15:57:34","publishedOnDateReadable":"May 20th, 2025"},"versionCreatedAt":"2024-12-09 04:49:35","video":"","vorDoi":"10.1038/s41598-025-02097-6","vorDoiUrl":"https://doi.org/10.1038/s41598-025-02097-6","workflowStages":[]},"version":"v1","identity":"rs-5039115","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5039115","identity":"rs-5039115","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}