mRNA vaccine platform demonstrates potent immunotherapeutic targeting of amyloid-β and tau pathologies in Alzheimer's disease

mRNA vaccine platform demonstrates potent immunotherapeutic targeting of amyloid-β and tau pathologies 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 mRNA vaccine platform demonstrates potent immunotherapeutic targeting of amyloid-β and tau pathologies in Alzheimer's disease Hui Wu, Yunyu Hou, Xuejian Feng, Xue Xia, Xianghui Yu, Wei Kong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7514957/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Current Alzheimer’s disease (AD) immunotherapeutics face efficacy and safety limitations with antibody-based approaches. While active immunization targeting Aβ and Tau pathologies represents a promising therapeutic avenue, existing peptide/protein vaccines fail to sustain adequate antibody titers or durable immune responses. mRNA vaccines offer a promising alternative, combining sustained immunogenicity, flexible antigen design, and favorable safety profiles. We developed an AD mRNA vaccine platform generating Aβ- and Tau-targeting candidates. These engineered vaccines induced robust, persistent antigen-specific antibodies in AD models without harmful T-cell responses or cerebrovascular complications. They mediated broad clearance of pathogenic aggregates across brain regions, resolved chronic neuroinflammation, and halted neurodegeneration-driven cognitive decline. Mechanistically, vaccine-induced antibodies crossed the blood-brain barrier, directly neutralized pathological proteins, enhanced microglial phagocytic activity, and modulated neuroinflammatory pathways, collectively restoring neuronal homeostasis. This mRNA platform overcomes key constraints of current clinical candidates by achieving potent pathological clearance while circumventing treatment-limiting toxicities, positioning mRNA-based active immunization as a transformative therapeutic strategy with near-term translational potential for AD. Biological sciences/Immunology/Vaccines/RNA vaccines Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted Version 1 posted 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7514957","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":515488785,"identity":"d9082b76-fb8f-40e1-a016-c2d5b8c7066e","order_by":0,"name":"Hui Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYLACxgYGHn6Gww1AJjNh1TwwLZINB0nUwmBwgJFILfbsvcekeXccljE+eLBNgqHCOrGB/ewB/LbwnEuT5j1zmMfsAEjLmfTEBp68BPxaJHLMbvO2QbUwth1ObJDgMSBOi3EDSMs/UrQYMIC0NBCj5cy59J9z29J5JA4cbLZIOJZu3MaTg18Le3vvYYO3bdb2/DMOH7zxocZatp/9DH4t0JgBAokDDAwJQJqNgHokLfwNhNWOglEwCkbByAQAQDFEhIFnj98AAAAASUVORK5CYII=","orcid":"","institution":"Jilin University","correspondingAuthor":true,"prefix":"","firstName":"Hui","middleName":"","lastName":"Wu","suffix":""},{"id":515488786,"identity":"2b453636-c842-4959-89b2-6698287dacf6","order_by":1,"name":"Yunyu Hou","email":"","orcid":"","institution":"Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Yunyu","middleName":"","lastName":"Hou","suffix":""},{"id":515488787,"identity":"718eff1d-e5ea-4b3f-87af-8e7e83eac45e","order_by":2,"name":"Xuejian Feng","email":"","orcid":"","institution":"Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Xuejian","middleName":"","lastName":"Feng","suffix":""},{"id":515488788,"identity":"a10973f4-0b60-4e7b-bc8e-9e9f17ae8a5a","order_by":3,"name":"Xue Xia","email":"","orcid":"","institution":"National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"Xia","suffix":""},{"id":515488789,"identity":"dfd6396f-455e-4474-bf42-6b28dcaba389","order_by":4,"name":"Xianghui Yu","email":"","orcid":"","institution":"Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Xianghui","middleName":"","lastName":"Yu","suffix":""},{"id":515488790,"identity":"9ac3df98-409f-424d-bdd2-10e9fb972aae","order_by":5,"name":"Wei Kong","email":"","orcid":"","institution":"Jilin University","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Kong","suffix":""}],"badges":[],"createdAt":"2025-09-02 08:01:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7514957/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7514957/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93158794,"identity":"ad193897-82fc-4af4-bf9c-7f8e54c9b787","added_by":"auto","created_at":"2025-10-09 16:08:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3588604,"visible":true,"origin":"","legend":"Article File","description":"","filename":"maintextandfigure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7514957/v1_covered_8b155f06-47d5-48e0-8e60-89231f54ce12.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"mRNA vaccine platform demonstrates potent immunotherapeutic targeting of amyloid-β and tau pathologies in Alzheimer's disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7514957/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7514957/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Current Alzheimer’s disease (AD) immunotherapeutics face efficacy and safety limitations with antibody-based approaches. While active immunization targeting Aβ and Tau pathologies represents a promising therapeutic avenue, existing peptide/protein vaccines fail to sustain adequate antibody titers or durable immune responses. mRNA vaccines offer a promising alternative, combining sustained immunogenicity, flexible antigen design, and favorable safety profiles. We developed an AD mRNA vaccine platform generating Aβ- and Tau-targeting candidates. These engineered vaccines induced robust, persistent antigen-specific antibodies in AD models without harmful T-cell responses or cerebrovascular complications. They mediated broad clearance of pathogenic aggregates across brain regions, resolved chronic neuroinflammation, and halted neurodegeneration-driven cognitive decline. 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