{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T07:00:57Z","timestamp":1777359657930,"version":"3.51.4"},"reference-count":57,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIH\/NINDS SC3 NS127765"],"award-info":[{"award-number":["NIH\/NINDS SC3 NS127765"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM152760"],"award-info":[{"award-number":["T32GM152760"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Microcirculation"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Microvascular hyperpermeability and blood\u2013brain barrier (BBB) dysfunction is a key consideration in neurological disorders, particularly\n                      <jats:italic>tauopathies,<\/jats:italic>\n                      a group of neurodegenerative disorders driven by misfolded and aggregated tau protein. Tau pathology has been shown to activate microglial NLRP3 inflammasome, an innate immune system sensor that responds to changes in the microenvironment, including cellular stress. Increases in reactive oxygen species (ROS), for example, activate NLRP3 inflammasome signaling, which provides a platform for the maturation of caspase\u20101 enzyme. Mature caspase\u20101 can cleave and release pro\u2010inflammatory IL\u20101\u03b2 cytokine. Both NLRP3 inflammasome and IL\u20101\u03b2 may activate downstream MMP\u20109 enzyme, a known inducer of endothelial cell barrier hyperpermeability. Endothelial cells make up the innermost layer of the BBB and as such, largely govern BBB structural and functional integrity. Whether tau can activate NLRP3 inflammasome signaling in cerebral endothelial cells is unknown. The objective of this study is therefore to understand the role of tau, in various states of aggregation, on endothelial cell permeability and to investigate if NLRP3 inflammasome signaling occurs in this context.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human brain microvascular endothelial cells (HBMECs) were grown as a monolayer in\n                      <jats:italic>Transwell<\/jats:italic>\n                      inserts and exposed to various tau polymorphs, including tau monomers, tau oligomers (oTau), and tau fibrils (fTau). Barrier permeability was measured using FITC\u2010dextran fluorescent tracer (10\u2009kDa) and Trans\u2010Endothelial Electrical Resistance (TEER). Relative changes in gene expression were measured using RT\u2010qPCR and normalized to GAPDH. Levels of NLRP3 sensor protein and IL\u20101\u03b2 were measured by ELISA. Relative activity of caspase\u20101 and MMP\u20109 enzymes was calculated using fluorometry. Cell viability was reported using calcein AM, a measure of cell membrane integrity, and by measuring the redox potential of XTT. ROS formation, apoptosis, and necrosis were determined using commercially available kits. An NLRP3 inflammasome inhibitor, MCC950, was applied in blocking studies prior to tau treatments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Tau oligomers, but not monomers or fibrils, induced endothelial cell hyperpermeability in a dose\u2010independent manner. At concentrations that compromised barrier function (100\u2009nM; overnight), oTau did not alter cell viability and did not increase apoptosis or necrosis. Tau oligomers increased the formation of ROS and increased levels of both NLRP3 sensor protein and IL\u20101\u03b2 cytokine. Enzymatic activity of caspase\u20101 and MMP\u20109 also increased in response to oTau, without changes in gene expression. These alterations were attenuated when NLRP3 inflammasome signaling was inhibited via MCC950, strongly suggesting that oTau activates NLRP3 inflammasome signaling in cerebral endothelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study is the first to document a role for NLRP3 inflammasome signaling in cerebral endothelial cells following exposure to tau oligomers. Given the importance of endothelial cell functioning in BBB integrity, these data are significant in that they demonstrate a key role for endothelial cell signaling in tau pathogenicity and propose a mechanism by which tauopathies compromise BBB functional integrity. Taken together, these findings warrant future investigation into the therapeutic potential of NLRP3 inflammasome inhibition to ameliorate tauopathy\u2010related barrier breach.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/micc.70059","type":"journal-article","created":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T10:50:02Z","timestamp":1777200602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tau Oligomers Induce Brain Endothelial Cell Hyperpermeability and Increase NLRP3 Inflammasome Signaling and MMP\u20109 Activity"],"prefix":"10.1111","volume":"33","author":[{"given":"Gabriela","family":"Seplovich","sequence":"first","affiliation":[{"name":"Department of Surgery Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saravanakumar","family":"Muthusamy","sequence":"additional","affiliation":[{"name":"Department of Surgery Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9115-5379","authenticated-orcid":false,"given":"Aliyah","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Surgery Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"O'lisa Yaa","family":"Waithe","sequence":"additional","affiliation":[{"name":"Department of Surgery Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Firas","family":"Kobeissy","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9343-6473","authenticated-orcid":false,"given":"Kevin K.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2004-1016","authenticated-orcid":false,"given":"Binu","family":"Tharakan","sequence":"additional","affiliation":[{"name":"Department of Surgery Morehouse School of Medicine  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13030260"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-015-2050-8"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0297-y"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20220830"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-024-00973-9"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00753-9"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1707-9"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2018.12.005"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15060824"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-07499-w"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06788-w"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/08977151251374286"},{"key":"e_1_2_11_14_1","doi-asserted-by":"crossref","unstructured":"F.Georgescauld S.Okekenwa T.Boyd et\u00a0al. \u201cDynamic Conformational Ensembles of Soluble Tau Encode Neuronal Toxicity Prior to Aggregation \u201dbioRxiv(2026) https:\/\/doi.org\/10.64898\/2026.01.26.701882.","DOI":"10.64898\/2026.01.26.701882"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2021461118"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-015-0186-2"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0217216"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2020.570045"},{"key":"e_1_2_11_19_1","first-page":"11","article-title":"Neuronal Inflammasomes: Balancing Immunity, Neuroinflammation, and Homeostasis","author":"Rivero Vaccari J. 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