Isotope Encoded Spatial Biology Identifies Amyloid Plaque-Age-Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity

Isotope Encoded Spatial Biology Identifies Amyloid Plaque-Age-Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity | 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 Isotope Encoded Spatial Biology Identifies Amyloid Plaque-Age-Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity Jörg Hanrieder, Jack Wood, Maciej Dulewicz, Junyue Ge, Katie Stringer, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5829037/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Sep, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Understanding how amyloid beta (Aβ) plaques form and progress to neurotoxicity in Alzheimer’s disease remains a significant challenge. This study aims to elucidate the processes involved in Aβ plaque formation and maturation using a knock-in Aβ mouse model (AppNL- F/NL-F). By employing mass spectrometry imaging and stable isotope labeling, we timestamped Aβ plaques from their initial deposition, enabling the spatial tracking of plaque aging. Correlating single-plaque spatial transcriptomics with time since seeding, allowed us to track gene-expression changes specifically associated with plaque age, independent of chronological age of the mouse or disease severity. We found that plaque age, within sections from individual mice aged from 10 to 18 months, negatively correlates with synaptic gene expression. Further, correlation with hyperspectral confocal microscopy using structure-specific dyes revealed a positive link between plaque age and structural maturity, with older plaques identified as more compact and associated with significantly greater synapse loss and toxicity. Biological sciences/Neuroscience/Neural ageing Biological sciences/Chemical biology/Chemical tools Biological sciences/Molecular biology/Transcription Full Text Additional Declarations Yes there is potential Competing Interest. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Cite Share Download PDF Status: Published Journal Publication published 01 Sep, 2025 Read the published version in Nature Communications → 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-5829037","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":405208736,"identity":"ab1db853-da13-4215-a190-a79887a55e7a","order_by":0,"name":"Jörg 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