Endothelial TRIM47 regulates blood-brain barrier integrity and cognition via the KEAP1/NRF2 signalling pathway

Endothelial TRIM47 regulates blood-brain barrier integrity and cognition via the KEAP1/NRF2 signalling pathway | 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 Endothelial TRIM47 regulates blood-brain barrier integrity and cognition via the KEAP1/NRF2 signalling pathway Claire Peghaire, Cécile Duplaà, Valentin Delobel, Romain Boulestreau, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6579058/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Feb, 2026 Read the published version in Communications Biology → Version 1 posted You are reading this latest preprint version Abstract Cerebral small vessel disease (cSVD) is a leading cause of stroke, cognitive decline and dementia, for which no specific mechanism-based treatments are currently available. Previous genomic studies identified associations of common variants at chr17q25 with cSVD features, with converging evidence for a causal involvement of TRIM47, an ubiquitin ligase enriched in brain endothelial cells (ECs). In the present study, we devised a multilayered experimental plan to decipher the biological mechanisms underlying TRIM47’s role in cSVD pathophysiology. Trim47-deficient mice, which model the human genetic anomaly, exhibit major cognitive impairments, increased blood-brain barrier (BBB) permeability, and astrogliosis, without neuroinflammation. Inducible deletion of Trim47 in ECs recapitulates these phenotypes highlighting the contribution of endothelial TRIM47 in maintaining brain homeostasis. In vitro and in vivo data, demonstrate that TRIM47 regulates the resilience of brain ECs to oxidative stress by binding to KEAP1, stabilizing NRF2 protein levels and promoting the NRF2 pathway. Treatment with the NRF2 activator tert-butylhydroquinone prevented BBB and cognitive impairment in Trim47-mutant mice. By leveraging unique human proteomic data, we propose that modulation of the TRIM47/NRF2 pathway could predict of a increased susceptibility to cSVD, suggesting that targeting this pathway may offer a promising therapeutic approach for vascular cognitive impairment and dementia. Biological sciences/Neuroscience/Blood–brain barrier Biological sciences/Neuroscience/Cognitive neuroscience/Cognitive control Health sciences/Neurology/Neurological disorders/Dementia Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryinformationTRIM47NRF2SVDpaperClairePEGHAIRE02052025.pdf Supplementary data Cite Share Download PDF Status: Published Journal Publication published 10 Feb, 2026 Read the published version in Communications Biology → 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-6579058","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":453255146,"identity":"a86c7a4f-34a1-4511-ac8e-69b9ba1c594c","order_by":0,"name":"Claire Peghaire","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3304-3018","institution":"Univ. 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