Distinct structural features associated with conformational epitopes of amyloid β fibrils revealed using mathematical geometric measures

Distinct structural features associated with conformational epitopes of amyloid β fibrils revealed using mathematical geometric measures | 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 Distinct structural features associated with conformational epitopes of amyloid β fibrils revealed using mathematical geometric measures Masumi Sugiyama, Shang-Te Danny Hsu, Eleni Panagiotou, Shin-ichi Tate This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9285528/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Monoclonal antibodies (mAbs) targeting the key pathogenic protein amyloid β (Aβ) peptide represent a promising therapeutic approach for treating Alzheimer’s disease (AD). Anti-Aβ mAbs are classified by their affinity to different states of Aβ, such as monomers, oligomers, protofibrils, and fibrils. Recently developed second-generation mAbs, which effectively remove Aβ plaques from the AD patients’ brains, exhibit specific avidity for Aβ oligomers, protofibrils, and fibrils. These mAbs target epitopes in specific conformations displayed on Aβ oligomers, protofibrils, or fibrils; thus, they are called conformational epitopes. However, the structural features of conformational epitopes are poorly understood. Here, we proposed geometric measures based on the mathematically defined writhe. We found that the conformational epitopes of Aβ in the 69 fibrils show distinctive geometric features compared to the other regions of Aβ, as evidenced by outlying values of the geometric measures. Mapping regions with higher measure values identifies potential conformational epitopes across various fibril forms. Results showed that some fibril forms exhibit geometrically distinct regions within the fibril structures, suggesting that these fibrils are less accessible to mAbs, impairing therapeutic effects targeting them. Our geometric measures reveal visually unidentified structural features of conformational epitopes in polymorphic Aβ fibrils, which relate to mAbs binding. Biological sciences/Biochemistry Biological sciences/Biophysics Biological sciences/Computational biology and bioinformatics Biological sciences/Neuroscience Biological sciences/Structural biology Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementarymaterialFinal02a.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 19 May, 2026 Reviewers agreed at journal 07 May, 2026 Reviews received at journal 27 Apr, 2026 Reviewers agreed at journal 17 Apr, 2026 Reviewers invited by journal 13 Apr, 2026 Editor invited by journal 07 Apr, 2026 Editor assigned by journal 03 Apr, 2026 Submission checks completed at journal 03 Apr, 2026 First submitted to journal 31 Mar, 2026 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-9285528","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":624992321,"identity":"3d8075a8-544d-4bf7-83d2-95aafc33931f","order_by":0,"name":"Masumi Sugiyama","email":"","orcid":"","institution":"Hiroshima University","correspondingAuthor":false,"prefix":"","firstName":"Masumi","middleName":"","lastName":"Sugiyama","suffix":""},{"id":624992322,"identity":"ac18f6fd-4180-453e-9060-e5c7d4185491","order_by":1,"name":"Shang-Te Danny Hsu","email":"","orcid":"","institution":"Academia Sinica","correspondingAuthor":false,"prefix":"","firstName":"Shang-Te","middleName":"Danny","lastName":"Hsu","suffix":""},{"id":624992323,"identity":"794aff5e-bd07-4dc0-9618-9373800af268","order_by":2,"name":"Eleni Panagiotou","email":"","orcid":"","institution":"Arizona State University","correspondingAuthor":false,"prefix":"","firstName":"Eleni","middleName":"","lastName":"Panagiotou","suffix":""},{"id":624992324,"identity":"76d9dcc0-018b-4c5e-9f28-eb6018438705","order_by":3,"name":"Shin-ichi Tate","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYLCCjw0SQJKH4QBcRAKPah4GZgbGmSRrYeZtgDCJA/bs5w8+tt1hkc/Pf/bgoRs1DIkN7IcfMFjuwGMLTzKzce4ZCcuZM/ISDuccA2rhSTNgkDyDz2HJbNK5bRIGBjd4DA7nsP1PbGDIYWCQbMOjhf8x+29LkJbzZ4Ba/gFt4X9DQItEMhszI0jLgRyDw7ltQC0ShGy58dhYsheoRXIGSEsfg3GbxDODA/j8wt6f+PDDz7Y6A37+M8afc74xyPbzJz98LIknxDABGxAflmwgRQsIMH4kWcsoGAWjYBQMYwAASBdJ2UUWVIgAAAAASUVORK5CYII=","orcid":"","institution":"Hiroshima University","correspondingAuthor":true,"prefix":"","firstName":"Shin-ichi","middleName":"","lastName":"Tate","suffix":""}],"badges":[],"createdAt":"2026-04-01 02:24:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9285528/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9285528/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107482698,"identity":"673e72f1-5cba-4d52-a0bd-3aea3e9dfefd","added_by":"auto","created_at":"2026-04-22 02:24:29","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":762913,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscriptmainv2.1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9285528/v1_covered_fae71a94-f388-4b06-8ef1-0976681a5dc0.pdf"},{"id":107183177,"identity":"f0111304-1af9-4cad-a484-6e0c26098ad0","added_by":"auto","created_at":"2026-04-17 18:07:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":25155402,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialFinal02a.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9285528/v1/d05525b600e5750f977a2dec.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Distinct structural features associated with conformational epitopes of amyloid β fibrils revealed using mathematical geometric measures","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"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":"","lastPublishedDoi":"10.21203/rs.3.rs-9285528/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9285528/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Monoclonal antibodies (mAbs) targeting the key pathogenic protein amyloid β (Aβ) peptide represent a promising therapeutic approach for treating Alzheimer’s disease (AD). 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