Rapid elongation drives the exceptionally fast aggregation of medin, the most common localized human amyloid

Rapid elongation drives the exceptionally fast aggregation of medin, the most common localized human amyloid | 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 Rapid elongation drives the exceptionally fast aggregation of medin, the most common localized human amyloid Michele Vendruscolo, Vaidehi Roy Chowdhury, Robert Horne, Mariana Cali, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6476074/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 Amyloid deposition is a hallmark of numerous age-related diseases, and understanding the chemical mechanisms that govern amyloid formation is crucial for advancing the rational development of protein aggregation inhibitors. With amyloid formation rates varying widely across proteins, here we report the quantitative aggregation mechanism of medin, the most common localized amyloid in humans, and find it to be extraordinarily faster compared to well-known pathological amyloids such as amyloid-β (Aβ), tau and ⍺-synuclein. Medin, a proteolytic fragment of lactadherin, forms senile localized amyloid deposits in the upper body vasculature of nearly all individuals over 60. We report the microscopic rate constants and reaction orders of medin fibril formation by monitoring the aggregation of recombinant human medin in vitro via a fluorescence-based assay, global kinetic modelling, secondary structure analysis and electron microscopy. Medin spontaneously forms amyloid fibrils at physiological pH and temperature in quiescent solution at concentrations as low as 25 nM, with the highest fibril elongation rate constant when compared to those of Aβ, tau and ⍺-synuclein. Our results identify the microscopic basis of the widespread observation of medin aggregates upon aging, offering a mechanistic starting point for drug discovery to inhibit medin aggregation. Biological sciences/Chemical biology Biological sciences/Biochemistry medin chemical kinetics supramolecular chemistry amyloid Alzheimer’s disease Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MedinaggregationmechanismSI.pdf Supplemental Material 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-6476074","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":502113559,"identity":"919532b4-c61f-4ea4-8a3c-db4bb565a395","order_by":0,"name":"Michele 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