Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus

Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus | 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 Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus Ruth Fabian-Fine, Abigail G. Roman, Melanie J. Winters, Kyleena J. Lathram, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9337412/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 According to the prevalent ‘Amyloid Hypothesis,’ the underlying cause for neurodegeneration in Alzheimer Disease (AD) is attributed to the accumulation of misfolded Amyloid ß and tau protein in the form of extracellular sticky plaques and neurofibrillary tangles, respectively. These protein accumulations are thought to be caused by impaired waste removal. In an alternative hypothesis, we have proposed the existence of an extensive glial canal system that is likely formed by myelinated aquaporin-4 (AQP4)-expressing tanycytes and removes cellular waste from the hippocampal formation. Here, we demonstrate that tanycyte-derived waste-internalizing receptacles are immunoreactive for Aß and emanate from specialized nucleus-like organelles in the following referred to as ‘tanysomes.’ Utilizing RNA-scope in situ hybridization, we demonstrate that these receptacle-forming tanysomes express RNA for AQP4 and the Aß-related genes, amyloid precursor protein, and presenilin-1. These findings suggest that Aß is likely synthesized where receptacle formation is observed and that Aß may play an important structural role in receptacle formation. In AD-affected hippocampus, excessive amounts of Aß-immunoreactive waste receptacles emerge from tanysomes and have the appearance of plaques in Aß-immunolabeled hippocampus. Moreover, we demonstrate that the same receptacle-forming organelles exhibit strong immunolabeling for hyperphosphorylated tau protein in AD-affected tissue. We postulate that both proteins may play important structural roles in waste uptake and that hypertrophic swelling of impaired tanycytes in AD-affected brain may be due to obstructions of this extensive interconnected glial canal system. Aquaporin 4 Myelin Tanycyte Convective flow Neurodegeneration Full Text Additional Declarations Competing interest reported. Dr. Fabian-Fine together with Saint Michael’s College holds a patent that directly resulted out of this research. The other co-authors on this paper have no conflict of 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-9337412","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":631287907,"identity":"bc4319ca-eb19-45f6-95b4-aa2fa0f07191","order_by":0,"name":"Ruth Fabian-Fine","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIie3PsQrCMBCA4ZPCuURdTyr6CoVCRQSfJaXgVBAnEUQEoS7i7OBzZLVS6DMIdWgXJxeXYhcxFdwk6uaQfwrHfSQB0On+MSNE4AANBKikryEpCfInaQZSW+WAfUVkzYU80lekGxjnNJ2dqG4u42nhD9w9GIeEKUgrxq7F4zNhKx4mNeG5a0CvryLUWTjEMZoj+U5SEaHNgDmmkmA1J36PCGmUj4snaeQfCHPIDUriI9RE2Ja34CcysdxNSYa2Kf/SZhHavZ36YSK75RF1tl52LcSAVVfL7HhRkDcZv63rdDqd7k0PWXJA0HBLdgkAAAAASUVORK5CYII=","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":true,"prefix":"","firstName":"Ruth","middleName":"","lastName":"Fabian-Fine","suffix":""},{"id":631287908,"identity":"80b596a9-4a08-4540-a4b5-ddf35bfb048f","order_by":1,"name":"Abigail G. Roman","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Abigail","middleName":"G.","lastName":"Roman","suffix":""},{"id":631287909,"identity":"2d5c9f49-4ccf-48c5-a46a-7a6d606446f1","order_by":2,"name":"Melanie J. Winters","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"J.","lastName":"Winters","suffix":""},{"id":631287910,"identity":"60285b0b-dee3-4d32-a053-2a82e3226466","order_by":3,"name":"Kyleena J. Lathram","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Kyleena","middleName":"J.","lastName":"Lathram","suffix":""},{"id":631287912,"identity":"fdeaad30-830c-4942-95d1-aef8d841668b","order_by":4,"name":"Carly H. Bennett","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Carly","middleName":"H.","lastName":"Bennett","suffix":""},{"id":631287913,"identity":"1c756f01-fc86-4729-8feb-af251caccdc5","order_by":5,"name":"Luwago K. Kipingi","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Luwago","middleName":"K.","lastName":"Kipingi","suffix":""},{"id":631287915,"identity":"53e18e43-5581-40bd-81d0-40eb84b32768","order_by":6,"name":"Sondre M. Brännare-Gran","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Sondre","middleName":"M.","lastName":"Brännare-Gran","suffix":""},{"id":631287917,"identity":"913196b7-7cf2-4fe5-9980-4f8373d9df30","order_by":7,"name":"Abigail E Whitley","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Abigail","middleName":"E","lastName":"Whitley","suffix":""},{"id":631287919,"identity":"372c96b0-0b64-46bc-a9ca-f24819f19dc0","order_by":8,"name":"Chloe M. Paul","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Chloe","middleName":"M.","lastName":"Paul","suffix":""},{"id":631287920,"identity":"3de60e37-6c65-48d6-9fab-a348245c1f71","order_by":9,"name":"Lydia M. Altman","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Lydia","middleName":"M.","lastName":"Altman","suffix":""},{"id":631287922,"identity":"38e28f92-8763-40c1-9a59-e9b54b335598","order_by":10,"name":"Ian C. Carrillo","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Ian","middleName":"C.","lastName":"Carrillo","suffix":""},{"id":631287924,"identity":"ff0f2225-170b-41e2-b804-01e407d84f09","order_by":11,"name":"Finn M. Joyce","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Finn","middleName":"M.","lastName":"Joyce","suffix":""},{"id":631287925,"identity":"ce29b0aa-43f3-498d-aa41-746608538f7a","order_by":12,"name":"Lydia A. Kragh","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Lydia","middleName":"A.","lastName":"Kragh","suffix":""},{"id":631287926,"identity":"47cea6af-c0d4-4232-aa5f-5dcb9881eadc","order_by":13,"name":"Theodore J. McKnight","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Theodore","middleName":"J.","lastName":"McKnight","suffix":""},{"id":631287927,"identity":"641ba511-a8ec-4758-867c-7af387a3154f","order_by":14,"name":"Calum J. Reding","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Calum","middleName":"J.","lastName":"Reding","suffix":""},{"id":631287929,"identity":"3da31810-d363-477e-9a29-2a4b68ee7da5","order_by":15,"name":"Leaf J. D. Reiderer","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Leaf","middleName":"J. D.","lastName":"Reiderer","suffix":""},{"id":631287930,"identity":"275ca46b-77ce-4223-a0d5-0feccdf41515","order_by":16,"name":"Lesley J. Rivera","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Lesley","middleName":"J.","lastName":"Rivera","suffix":""},{"id":631287934,"identity":"975e8a04-8b73-4d95-ab9c-4e52094d71bf","order_by":17,"name":"Hannah A. Steen","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Hannah","middleName":"A.","lastName":"Steen","suffix":""},{"id":631287935,"identity":"67ef9902-a439-4f0b-a96d-de98123e3e67","order_by":18,"name":"Adam L. Weaver","email":"","orcid":"","institution":"Saint Michael’s College","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"L.","lastName":"Weaver","suffix":""}],"badges":[],"createdAt":"2026-04-06 21:53:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9337412/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9337412/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108799568,"identity":"6fb5be3d-0db6-45ca-b086-b685e648215d","added_by":"auto","created_at":"2026-05-08 13:59:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2262502,"visible":true,"origin":"","legend":"","description":"","filename":"FabianFineetal2026InvisibleGiantSubmissionfile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9337412/v1_covered_e1430a60-21e1-4960-9b58-afb930bc24f5.pdf"}],"financialInterests":"Competing interest reported. Dr. Fabian-Fine together with Saint Michael’s College holds a patent that directly resulted out of this research. The other co-authors on this paper have no conflict of interest.","formattedTitle":"Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Aquaporin 4, Myelin, Tanycyte, Convective flow, Neurodegeneration","lastPublishedDoi":"10.21203/rs.3.rs-9337412/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9337412/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"According to the prevalent ‘Amyloid Hypothesis,’ the underlying cause for neurodegeneration in Alzheimer Disease (AD) is attributed to the accumulation of misfolded Amyloid ß and tau protein in the form of extracellular sticky plaques and neurofibrillary tangles, respectively. These protein accumulations are thought to be caused by impaired waste removal. In an alternative hypothesis, we have proposed the existence of an extensive glial canal system that is likely formed by myelinated aquaporin-4 (AQP4)-expressing tanycytes and removes cellular waste from the hippocampal formation. Here, we demonstrate that tanycyte-derived waste-internalizing receptacles are immunoreactive for Aß and emanate from specialized nucleus-like organelles in the following referred to as ‘tanysomes.’ Utilizing RNA-scope in situ hybridization, we demonstrate that these receptacle-forming tanysomes express RNA for AQP4 and the Aß-related genes, amyloid precursor protein, and presenilin-1. These findings suggest that Aß is likely synthesized where receptacle formation is observed and that Aß may play an important structural role in receptacle formation. In AD-affected hippocampus, excessive amounts of Aß-immunoreactive waste receptacles emerge from tanysomes and have the appearance of plaques in Aß-immunolabeled hippocampus. Moreover, we demonstrate that the same receptacle-forming organelles exhibit strong immunolabeling for hyperphosphorylated tau protein in AD-affected tissue. We postulate that both proteins may play important structural roles in waste uptake and that hypertrophic swelling of impaired tanycytes in AD-affected brain may be due to obstructions of this extensive interconnected glial canal system.","manuscriptTitle":"Uncovering the invisible giant: Amyloid beta plaques and their proposed association with waste removal in Alzheimer-affected human hippocampus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-30 19:11:01","doi":"10.21203/rs.3.rs-9337412/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","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}}],"origin":"","ownerIdentity":"86c0fd95-fa9a-4baa-8a2b-f0e5ed53e04b","owner":[],"postedDate":"April 30th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-08T13:48:35+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-06T17:26:55+00:00","index":21,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T13:57:44+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-30 19:11:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9337412","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9337412","identity":"rs-9337412","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}