Microvascular dysfunction and aberrant network activity drive reduced brain oxygenation in a mouse tauopathy model

Microvascular dysfunction and aberrant network activity drive reduced brain oxygenation in a mouse tauopathy model | 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 Microvascular dysfunction and aberrant network activity drive reduced brain oxygenation in a mouse tauopathy model Costantino Iadecola, Sung Ji Ahn, Antoine Anfray, Yun Losson, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8205391/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 Tauopathies such as Alzheimer’s disease and frontotemporal dementia are leading causes of cognitive impairment, characterized by accumulation of hyperphosphorylated tau, a microtubule-associated protein, in brain. In addition to driving neural network hyperactivity and neuronal damage, tau disrupts neurovascular function, which may further contribute to disease pathogenesis. Using a mouse tauopathy model, we demonstrate that tau causes a profound breakdown of the normally well-coordinated segmental vasodilation induced by neural activity, resulting in dampened and delayed blood-flow increases, heterogeneous capillary perfusion, and frequent capillary stalling. These neurovascular alterations arise in the context of pronounced network hyperactivity and hypersynchrony, which combined with impaired neurovascular coupling, lead to reduced oxygen availability, episodic hypoxia, and disturbed metabolic homeostasis. Collectively, these findings identify reduced brain oxygenation driven by an imbalance between neuronal hyperactivity and diminished oxygen delivery as a previously-unappreciated early pathogenic consequence of tau accumulation and bolster the rationale for therapies to restore cerebral oxygenation. Biological sciences/Neuroscience/Neuro–vascular interactions Biological sciences/Neuroscience/Diseases of the nervous system/Neurodegeneration Biological sciences/Neuroscience/Diseases of the nervous system/Alzheimer's disease Biological sciences/Neuroscience/Somatosensory system/Barrel cortex neurovascular coupling nNOS excitation-inhibition imbalance O2 phosphorescence lifetime imaging capillary stalling capillary transit time heterogeneity Full Text Additional Declarations Yes there is potential Competing Interest. C.I. is on the scientific advisory board of Broadview Ventures. 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-8205391","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":562939847,"identity":"fc4007fc-3e60-4063-8909-a54736cb0e91","order_by":0,"name":"Costantino Iadecola","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYFACxsYHCQYSckCWAUSAnbmBgYENr5Zmgw8VFsYILcyMhLQwsEnOOFOR2EC0Fv725gZp3jaJ9LXtzRsYflTcy+MHaflQdhinFokzBxuMgVpyt505VsDYc6a4WLKZsYFxxjncWgwkEhuSwVpu5BgwM7YlJG44zNjAzNuGX8thkMPM7r+BaNkP0vIXv5bGxhlnJBLMbvBAbQH6BcjA65dmhg8VEobbzqQVHOw5k5A4A2jLwZ5z6Ti18Le3P/+RYFAnb3b88MYHPyoSEvvbmw8++FFmjVMLCjiAwRgFo2AUjIJRQB4AAE7TWlNWFW09AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-9797-073X","institution":"Weill Cornell Medicine","correspondingAuthor":true,"prefix":"","firstName":"Costantino","middleName":"","lastName":"Iadecola","suffix":""},{"id":562939848,"identity":"b4f8bab4-d98a-46a2-86e6-b28b97f52a0c","order_by":1,"name":"Sung Ji Ahn","email":"","orcid":"https://orcid.org/0000-0001-8836-8069","institution":"Weill Cornell Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sung","middleName":"Ji","lastName":"Ahn","suffix":""},{"id":562939849,"identity":"32d86029-6bf1-4b05-a25d-16a94391f914","order_by":2,"name":"Antoine Anfray","email":"","orcid":"","institution":"Weill Cornell Medicine","correspondingAuthor":false,"prefix":"","firstName":"Antoine","middleName":"","lastName":"Anfray","suffix":""},{"id":562939850,"identity":"08834885-705a-4471-b573-e786480990b8","order_by":3,"name":"Yun Losson","email":"","orcid":"","institution":"Weill Cornell Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Losson","suffix":""},{"id":562939851,"identity":"03a4ec4d-f8d7-48ee-814e-cececf6307f0","order_by":4,"name":"Liping Qian","email":"","orcid":"","institution":"Weill Cornell Medical College","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Qian","suffix":""},{"id":562939852,"identity":"d81eb615-a6c8-4671-950a-6c1ff1905c1d","order_by":5,"name":"Belem Yoval-Sánchez","email":"","orcid":"","institution":"Weill Cornell Medicine","correspondingAuthor":false,"prefix":"","firstName":"Belem","middleName":"","lastName":"Yoval-Sánchez","suffix":""},{"id":562939853,"identity":"99456580-5e8d-46d1-8f8d-936b912e17f6","order_by":6,"name":"Gang Wang","email":"","orcid":"","institution":"Feil Family Brain and Mind Research Institute - 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