MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages

MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages | 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 MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages Alison Goate, Anna Podlesny-Drabiniok, Jeanne Kim, Lotte Bezemer, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9164252/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 Risk alleles for late-onset Alzheimer’s disease (AD) are enriched in myeloid cis-regulatory elements, implicating myeloid gene-regulatory networks in disease susceptibility. A conserved lipid-associated transcriptional signature—spanning disease-associated microglia and peripheral lipid-associated macrophages (DLAM)—emerges across neurodegenerative and metabolic diseases characterized by lipid overload, yet the transcriptional regulators of this gene expression program remain incompletely defined. Here, we show that MEF2C—a candidate AD risk gene—is a master DLAM regulator. Using MEF2C knockout and knockdown in human iPSC-derived microglia and macrophages, we found that total or partial MEF2C loss is sufficient to induce DLAM-associated transcriptional, epigenomic, and functional remodeling, including enhanced lysosomal activity and cholesterol efflux. Integration of chromatin accessibility and regulatory epigenetic profiles with functionally informed fine-mapping linked candidate causal variants in AD risk loci to MEF2C-regulated cis-regulatory elements that target candidate AD risk genes at these loci. In a triculture model of AD, microglial MEF2C loss is associated with an increased DLAM population and a reduced Aβ42/40 ratio, supporting context-dependent reprogramming of microglia as a potential biological mechanism to modulate AD-relevant pathology. Biological sciences/Neuroscience/Neuroimmunology Health sciences/Diseases/Neurological disorders/Dementia/Alzheimer's disease Full Text Additional Declarations Yes there is potential Competing Interest. A.M.G.: Scientific Advisory Board (SAB) Genentech; SAB Muna Therapeutics Supplementary Files SupplementaryFile1Descriptivestatistics.docx Supplementary File 1 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. 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-9164252","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":629229700,"identity":"0f501703-530e-4094-af7b-3c330c90fe97","order_by":0,"name":"Alison Goate","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYDACdsYGBOcDlJbAq4UZroWZgXEGcVqQWMw8xGjhb2Zu/vBxB4NdP/v5g49tc+rsdRuYD97mwaNF4jBjm+TMMwzJM3uSmY1ztx1O3HaALdkanxYGoBZm3jaGZIMDyWzSudsOJJgd4DGTxqdF/jBj82ewlvOP2X9bbquzNzvA/w2vFoPDjA3SQC12BjeS2ZgZtwHRAR42vFoMwX5pk0iQnPHYWLIX5JfDbMaWc/BokTve/vjDxzYbe37+xIcffoIcdrz54Y03+LwPARKJDXA2M25lKMCeSHWjYBSMglEwEgEA9u9H+BQ+nBYAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0576-2472","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":true,"prefix":"","firstName":"Alison","middleName":"","lastName":"Goate","suffix":""},{"id":629229701,"identity":"76a8d39a-349c-42b7-9e42-bb10de1b15da","order_by":1,"name":"Anna Podlesny-Drabiniok","email":"","orcid":"https://orcid.org/0000-0001-5009-2263","institution":"Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Podlesny-Drabiniok","suffix":""},{"id":629229702,"identity":"cab2312f-5614-4e52-a241-7ab9c20f5970","order_by":2,"name":"Jeanne Kim","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Jeanne","middleName":"","lastName":"Kim","suffix":""},{"id":629229703,"identity":"08c3409c-643d-4c78-b05b-95bfe4bd4035","order_by":3,"name":"Lotte Bezemer","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Lotte","middleName":"","lastName":"Bezemer","suffix":""},{"id":629229704,"identity":"3287ee4b-e7c3-4fed-8541-352779a2026f","order_by":4,"name":"Tulsi Patel","email":"","orcid":"https://orcid.org/0000-0002-2797-1443","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Tulsi","middleName":"","lastName":"Patel","suffix":""},{"id":629229705,"identity":"2e13fe7a-b057-4efe-8cd0-03baeb608846","order_by":5,"name":"Haoxiang Cheng","email":"","orcid":"https://orcid.org/0000-0002-1393-6006","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Haoxiang","middleName":"","lastName":"Cheng","suffix":""},{"id":629229706,"identity":"47f64976-e271-4ecf-ad2a-ebee947ba223","order_by":6,"name":"Michael Sewell","email":"","orcid":"https://orcid.org/0000-0003-0113-6551","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Sewell","suffix":""},{"id":629229707,"identity":"0ace3ed2-754d-4e93-a7b2-a8b406ab5074","order_by":7,"name":"Mia Montecillo","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Mia","middleName":"","lastName":"Montecillo","suffix":""},{"id":629229708,"identity":"16c988ce-db72-44e8-b161-5f85ff65f582","order_by":8,"name":"Nicholas Church","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Nicholas","middleName":"","lastName":"Church","suffix":""},{"id":629229709,"identity":"658993c1-c909-458a-80c5-2a23009b7dbe","order_by":9,"name":"Anthony Walley","email":"","orcid":"","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Walley","suffix":""},{"id":629229710,"identity":"5c28c4d7-721c-415f-bee4-a89f55206ace","order_by":10,"name":"Francesca Garretti","email":"","orcid":"https://orcid.org/0000-0002-6609-8034","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Garretti","suffix":""},{"id":629229711,"identity":"86d47e7b-265b-4f92-85e0-4ab5a6e77407","order_by":11,"name":"Edoardo Marcora","email":"","orcid":"https://orcid.org/0000-0002-3829-4927","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Edoardo","middleName":"","lastName":"Marcora","suffix":""}],"badges":[],"createdAt":"2026-03-19 03:05:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9164252/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9164252/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108007393,"identity":"78fa7a18-5437-451b-846e-7aa6ed4da8ac","added_by":"auto","created_at":"2026-04-28 12:59:48","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":23089941,"visible":true,"origin":"","legend":"Article File","description":"","filename":"MEF2Cmanuscript16032026.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9164252/v1_covered_2cdb98b1-0fa8-4dd0-b2ee-4d73aa17432a.pdf"},{"id":107958934,"identity":"4f6620d1-d1d3-4a57-87a5-427de25bf8d8","added_by":"auto","created_at":"2026-04-28 03:52:13","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":222733,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary File 1\u003c/p\u003e","description":"","filename":"SupplementaryFile1Descriptivestatistics.docx","url":"https://assets-eu.researchsquare.com/files/rs-9164252/v1/d72a4a7a3b2dd80be31397df.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nA.M.G.: Scientific Advisory Board (SAB) Genentech; SAB Muna Therapeutics","formattedTitle":"MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9164252/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9164252/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Risk alleles for late-onset Alzheimer’s disease (AD) are enriched in myeloid cis-regulatory elements, implicating myeloid gene-regulatory networks in disease susceptibility. A conserved lipid-associated transcriptional signature—spanning disease-associated microglia and peripheral lipid-associated macrophages (DLAM)—emerges across neurodegenerative and metabolic diseases characterized by lipid overload, yet the transcriptional regulators of this gene expression program remain incompletely defined. Here, we show that MEF2C—a candidate AD risk gene—is a master DLAM regulator. Using MEF2C knockout and knockdown in human iPSC-derived microglia and macrophages, we found that total or partial MEF2C loss is sufficient to induce DLAM-associated transcriptional, epigenomic, and functional remodeling, including enhanced lysosomal activity and cholesterol efflux. Integration of chromatin accessibility and regulatory epigenetic profiles with functionally informed fine-mapping linked candidate causal variants in AD risk loci to MEF2C-regulated cis-regulatory elements that target candidate AD risk genes at these loci. In a triculture model of AD, microglial MEF2C loss is associated with an increased DLAM population and a reduced Aβ42/40 ratio, supporting context-dependent reprogramming of microglia as a potential biological mechanism to modulate AD-relevant pathology.","manuscriptTitle":"MEF2C controls lysosomal and lipid clearance programs linked to Alzheimer’s disease risk in macrophages","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-28 03:52:09","doi":"10.21203/rs.3.rs-9164252/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-neuroscience","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"neuro","sideBox":"Learn more about [Nature Neuroscience](http://www.nature.com/neuro/)","snPcode":"","submissionUrl":"","title":"Nature Neuroscience","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fa57ed57-85de-47e8-b541-2fbbbdfd043e","owner":[],"postedDate":"April 28th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-04T21:16:42+00:00","index":4,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66978395,"name":"Biological sciences/Neuroscience/Neuroimmunology"},{"id":66978396,"name":"Health sciences/Diseases/Neurological disorders/Dementia/Alzheimer's disease"}],"tags":[],"updatedAt":"2026-04-28T03:52:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-28 03:52:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9164252","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9164252","identity":"rs-9164252","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}