Large extracellular vesicles containing mitochondria (EVMs) derived from Alzheimer’s disease cells harbor pathologic functional and molecular profiles and spread mitochondrial dysfunctions

Large extracellular vesicles containing mitochondria (EVMs) derived from Alzheimer’s disease cells harbor pathologic functional and molecular profiles and spread mitochondrial dysfunctions | 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 Large extracellular vesicles containing mitochondria (EVMs) derived from Alzheimer’s disease cells harbor pathologic functional and molecular profiles and spread mitochondrial dysfunctions Fanny Eysert, Véronique Legros, Anne-Sophie Gay, Delphine Debayle, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5932075/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 In addition to small extracellular vesicles known as exosomes, cells release large extracellular vesicles containing mitochondria (EVMs). The molecular and functional characteristics of EVMs, as well as the impact of EVMs on the spreading of mitochondrial dysfunction between cells, remain unknown in the context of Alzheimer’s Disease (AD). Here, we provide an ultrastructural, biochemical, and functional characterization of EVMs isolated from neuroblastoma cells expressing the amyloid precursor protein with the familial Swedish mutations (APPswe). We identify differential proteomic and lipidomic signatures in APPswe-derived EVMs compared to control EVMs and revealed a specific proteomic profile in EVMs derived from fibroblasts of AD patients at the prodromal stage of the disease. Our findings show that the pathogenic accumulation of APP-C terminal fragments (APP-CTFs) potentiates the secretion of EVMs through plasma membrane budding. We demonstrate that APP-CTFs loaded EVMs are active carriers of dysfunctional mitochondria mediating the transfer of mitochondrial pathology between cells. Biological sciences/Cell biology/Organelles/Mitochondria/Energy metabolism Biological sciences/Cell biology/Mechanisms of disease Alzheimer’s disease Amyloid precursor protein APP-CTFs Extracellular vesicles- containing mitochondria Mitochondria Full Text Additional Declarations There is NO Competing Interest. Supplementary Files PatientsADMCIvsADDProtMitoSup1peptidepValue0.05Log2FC0.5.xlsx Patients_AD-MCIvsAD-D_ProtMito_Sup1peptide_pValue0.05_Log2FC-0.5.xlsx PatientsADMCIvsCTRLProtTOTALSup1peptidepValue0.05.xlsx Patients_AD-MCIvsCTRL_ProtTOTAL_Sup1peptide_pValue0.05.xlsx PatientsADDvsCTRLProtTOTALSup1peptidepValue0.05.xlsx Patients_AD-DvsCTRL_ProtTOTAL_Sup1peptide_pValue0.05.xlsx PatientsADDvsCTRLProtMitoSup1peptidepValue0.05Log2FC0.5.xlsx Patients_AD-DvsCTRL_ProtMito_Sup1peptide_pValue0.05_Log2FC-0.5.xlsx APPvsP3ProtTOTALSup3peptidespValue0.01Log2FC1.xlsx APPvsP3_ProtTOTAL_Sup3peptides_pValue0.01_Log2FC-1.xlsx PatientsADMCIvsADDProtTOTALSup1peptidepValue0.05.xlsx Patients_AD-MCIvsAD-D_ProtTOTAL_Sup1peptide_pValue0.05.xlsx PatientsADMCIvsCTRLProtMitoSup1peptidepValue0.05Log2FC0.5.xlsx Patients_AD-MCIvsCTRL_ProtMito_Sup1peptide_pValue0.05_Log2FC-0.5.xlsx APPvsP3ProtMitoSup3peptidespValue0.01Log2FC0.5.xlsx APPvsP3_ProtMito_Sup3peptides_pValue0.01_Log2FC-0.5.xlsx 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-5932075","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":414396122,"identity":"9ddc535a-6e20-4d1b-90ad-1e524985876a","order_by":0,"name":"Fanny Eysert","email":"","orcid":"","institution":"Université Côte d'Azur-CNRS UMR7275-INSERM U1323","correspondingAuthor":false,"prefix":"","firstName":"Fanny","middleName":"","lastName":"Eysert","suffix":""},{"id":414396123,"identity":"4541bdcd-2f33-4eaf-8f29-ba8ba3d51bdb","order_by":1,"name":"Véronique Legros","email":"","orcid":"","institution":"CNRS, Institut Jacques Monod, Université Paris 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The molecular and functional characteristics of EVMs, as well as the impact of EVMs on the spreading of mitochondrial dysfunction between cells, remain unknown in the context of Alzheimer’s Disease (AD). Here, we provide an ultrastructural, biochemical, and functional characterization of EVMs isolated from neuroblastoma cells expressing the amyloid precursor protein with the familial Swedish mutations (APPswe). We identify differential proteomic and lipidomic signatures in APPswe-derived EVMs compared to control EVMs and revealed a specific proteomic profile in EVMs derived from fibroblasts of AD patients at the prodromal stage of the disease. Our findings show that the pathogenic accumulation of APP-C terminal fragments (APP-CTFs) potentiates the secretion of EVMs through plasma membrane budding. 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