{"paper_id":"3df0a047-e0e8-4327-976a-7591c78e94eb","body_text":"Rejuvenation of senescent microglia using glucagon-like peptide-1 receptor agonist attenuates Alzheimer’s disease-like pathologies and behavioral deficits in aged 5xFAD mice 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 Article Rejuvenation of senescent microglia using glucagon-like peptide-1 receptor agonist attenuates Alzheimer’s disease-like pathologies and behavioral deficits in aged 5xFAD mice model Young-Sun Lee, Yu-Lim Seo, Gyun Jee Song, Kyoung Sang Cho, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6546219/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Aging is associated with cellular senescence, wherein cells lose their replicative ability. Cellular senescence may contribute to various aging-related diseases, such as Alzheimer’s disease (AD). In this study, we investigated the therapeutic potential of glucagon-like peptide-1 receptor (GLP-1R) agonist in attenuating AD-like pathologies by targeting cellular senescence in microglia. Senescent microglia exhibited reduced GLP-1 secretion, increased senescence marker levels, and impaired phagocytic and metabolic functions. GLP-1R agonist treatment attenuated these conditions by reducing senescence markers and promoting microglial phagocytosis of amyloid-beta plaques. Furthermore, GLP-1R agonist treatment restored microglial function by enhancing oxidative phosphorylation and reducing lipid accumulation. In vivo GLP-1R agonist treatment showed improvements in cognitive function in 5xFAD mice, including spatial memory and novel object recognition, and decreased senescent microglia in the brain. Thus, GLP-1R agonists can be potential senotherapeutic agents for AD, which can be used to rejuvenate senescent microglia. Biological sciences/Neuroscience/Glial biology/Microglia Biological sciences/Neuroscience/Cognitive ageing GLP-1R agonist senescence microglia Alzheimer’s disease Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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. 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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-6546219\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":454322996,\"identity\":\"a0741ecc-d3a5-482b-bcff-a75b3c68f49e\",\"order_by\":0,\"name\":\"Young-Sun Lee\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYBACA2YGxgMMDDYJYF5CAXFaGIBa0qBaDIAEGyEtDGAthxMQXEJazNmZDxzm+XM+j392d+KHBwYMefzyDfi1WDazJRzmbbtdLHHn7GYJoMOKJdsIOewwj8Fh3obbiQ03cjeAtCRuOEaMFp4/5xLn38jd/AOkZT9xWtgOJG64kbsNYgsh74P8cnBuW3LiRqAWiwQDicQZxxLwazHnP3zwwZs/donzgA67+aPCJrG/+QABa4CAiQfBliCsHAQYfxCnbhSMglEwCkYqAADZXUkn/V2LVgAAAABJRU5ErkJggg==\",\"orcid\":\"https://orcid.org/0000-0002-2342-6093\",\"institution\":\"Department of Medical Science, College of Medicine. Catholic Kwandong University\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Young-Sun\",\"middleName\":\"\",\"lastName\":\"Lee\",\"suffix\":\"\"},{\"id\":454322997,\"identity\":\"956b0282-d866-4d57-a1af-8e9ffaeffbc5\",\"order_by\":1,\"name\":\"Yu-Lim Seo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Department of Medical Science, College of Medicine. Catholic Kwandong University\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yu-Lim\",\"middleName\":\"\",\"lastName\":\"Seo\",\"suffix\":\"\"},{\"id\":454322998,\"identity\":\"4c3cf4e7-fb95-4b60-bc80-2fcf3ecfc43b\",\"order_by\":2,\"name\":\"Gyun Jee Song\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Department of Medical Science, College of Medicine. 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Cellular senescence may contribute to various aging-related diseases, such as Alzheimer\\u0026rsquo;s disease (AD). In this study, we investigated the therapeutic potential of glucagon-like peptide-1 receptor (GLP-1R) agonist in attenuating AD-like pathologies by targeting cellular senescence in microglia. Senescent microglia exhibited reduced GLP-1 secretion, increased senescence marker levels, and impaired phagocytic and metabolic functions. GLP-1R agonist treatment attenuated these conditions by reducing senescence markers and promoting microglial phagocytosis of amyloid-beta plaques. Furthermore, GLP-1R agonist treatment restored microglial function by enhancing oxidative phosphorylation and reducing lipid accumulation. \\u003cem\\u003eIn vivo\\u003c/em\\u003e GLP-1R agonist treatment showed improvements in cognitive function in 5xFAD mice, including spatial memory and novel object recognition, and decreased senescent microglia in the brain. 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