{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:00:58Z","timestamp":1791615658712,"version":"4.3.4"},"posted":{"date-parts":[[2025,1,27]]},"group-title":"Cell Biology","reference-count":155,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimer\u2019s disease (AD), particularly in individuals carrying the\n                  <jats:italic>APOE-\u03b54<\/jats:italic>\n                  allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (A\u03b242), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly in\n                  <jats:italic>APOE-\u03b54<\/jats:italic>\n                  carriers. Furthermore, we found a loss-of-function variant in the fibronectin 1 (\n                  <jats:italic>FN1<\/jats:italic>\n                  ) gene significantly reduces aggregated fibronectin levels and decreases AD risk among\n                  <jats:italic>APOE-\u03b54<\/jats:italic>\n                  carriers. Yet, the molecular mechanisms downstream of fibronectin at the BBB remain unclear. The extracellular matrix (ECM) plays a crucial role in maintaining BBB homeostasis and orchestrating the interactions between BBB cell types, including endothelia and astrocytes. Understanding the mechanisms affecting the ECM and BBB cell types will be critical for developing effective therapies against AD, especially among\n                  <jats:italic>APOE-\u03b54<\/jats:italic>\n                  carriers. Here, we demonstrate that\n                  <jats:italic>APOE-\u03b54<\/jats:italic>\n                  , A\u03b242, and inflammation drive the induction of\n                  <jats:italic>FN1<\/jats:italic>\n                  expression in several models including zebrafish, mice, iPSC-derived human 3D astrocyte and 3D cerebrovascular cell cultures, and in human brains. Fibronectin accumulation disrupts astroglial-endothelial interactions and the signalling cascade between vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor (HBEGF) and Insulin-like growth factor 1 (IGF1). This accumulation of fibronectin in\n                  <jats:italic>APOE-\u03b54-<\/jats:italic>\n                  associated AD potentiates BBB dysfunction, which strongly implicates reducing fibronectin deposition as a potential therapeutic target for AD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"634732v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Accessibility text<\/jats:title>\n                  <jats:p>This image illustrates the effects of different APOE isoforms (ApoE-\u03b53 and ApoE-\u03b54) on blood-brain barrier (BBB) integrity, focusing on the molecular interactions between astrocytes and endothelial cells. This figure emphasizes the detrimental effects of ApoE-\u03b54 on BBB integrity via fibronectin accumulation and altered signaling pathways.<\/jats:p>\n                  <jats:p>\n                    The\n                    <jats:bold>top section<\/jats:bold>\n                    provides a schematic overview of the blood-brain barrier, highlighting astrocytes, endothelial cells, and their interface.\n                  <\/jats:p>\n                  <jats:p>\n                    The\n                    <jats:bold>left panel<\/jats:bold>\n                    represents the ApoE-\u03b53 condition: Normal fibronectin (FN1) levels support healthy interactions between astrocytes and endothelial cells. Growth factors, including VEGFA, HBEGF, and IGF1, maintain BBB integrity through their respective receptors (VEGFR and EGFR). Green arrows indicate activation of these signaling pathways.\n                  <\/jats:p>\n                  <jats:p>\n                    The\n                    <jats:bold>right panel<\/jats:bold>\n                    depicts the ApoE-\u03b54 condition: Elevated fibronectin (FN1) disrupts astrocyte-endothelium interactions. FN1 binds integrins and activates focal adhesion kinase (FAK), inhibiting VEGFA, which is required for endothelial HBEGF that in turn activates IGF1 signaling. Red symbols indicate inhibition of HBEGF, VEGFA, and IGF1 pathways, leading to BBB dysfunction.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:p>\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    drives fibronectin deposition in Alzheimer\u2019s, disrupting astrocyte-endothelia interactions.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    and fibronectin co-localize, forming aggregates at blood-brain barrier (BBB).\n                  <\/jats:p>\n                  <jats:p>Fibronectin alters the signaling between VEGF, IGF1, and HBEGF impairing BBB function.<\/jats:p>\n                  <jats:p>\n                    Reducing fibronectin restores BBB integrity and offsets\n                    <jats:italic>APOE-\u03b54<\/jats:italic>\n                    pathology.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.01.24.634732","type":"posted-content","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T11:05:25Z","timestamp":1737975925000},"source":"Crossref","is-referenced-by-count":11,"title":["<i>APOE-<\/i>\n                  \u03b54-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2991-5514","authenticated-orcid":false,"given":"Prabesh","family":"Bhattarai","sequence":"first","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7045-5068","authenticated-orcid":false,"given":"Elanur","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif \u00d6yk\u00fc","family":"Cakir","sequence":"additional","affiliation":[{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hande Y\u00fcceer","family":"Korkmaz","sequence":"additional","affiliation":[{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"Department of Pathology and Cell Biology, Columbia University Irving Medical Center; New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"The Taub Institute for Research on Alzheimer\u2019s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"The Gertrude H. 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