{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:41:27Z","timestamp":1791510087841,"version":"4.3.4"},"reference-count":41,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,7]],"date-time":"2024-01-07T00:00:00Z","timestamp":1704585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>INTRODUCTION<\/jats:title>\n                    <jats:p>\n                      Genome\u2010wide association studies link susceptibility to late\u2010onset Alzheimer's disease (LOAD) with\n                      <jats:italic>EphA<\/jats:italic>\n                      1. Sequencing identified a non\u2010synonymous substitution P460L as a LOAD risk variant. Other Ephs regulate vascular permeability and immune cell recruitment. We hypothesized that P460L dysregulates EphA1 receptor activity and impacts neuroinflammation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>EphA1\/P460L receptor activity was assayed in isogenic Human Embryonic Kidney (HEK) cells. Soluble EphA1\/P460L (sEphA1\/sP460L) reverse signaling in brain endothelial cells was assessed by T\u2010cell recruitment and barrier function assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>EphA1 and P460L were expressed in HEK cells, but membrane and soluble P460L were significantly reduced. Ligand engagement induced Y781 phosphorylation of EphA1 but not P460L. sEphA1 primed brain endothelial cells for increased T\u2010cell recruitment; however, sP460L was less effective. sEphA1 decreased the integrity of the brain endothelial barrier, while sP460L had no effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>These findings suggest that P460L alters EphA1\u2010dependent forward and reverse signaling, which may impact blood\u2010brain barrier function in LOAD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>EphA1\u2010dependent reverse signaling controls recruitment of T cells by brain endothelial cells.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>EphA1\u2010dependent reverse signaling remodels brain endothelial cell contacts.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>LOAD\u2010associated P460L variant of EphA1 shows reduced membrane expression and reduced ligand responses.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>LOAD\u2010associated P460L variant of EphA1 fails to reverse signal to brain endothelial cells.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.13603","type":"journal-article","created":{"date-parts":[[2024,1,7]],"date-time":"2024-01-07T05:05:06Z","timestamp":1704603906000},"page":"2016-2033","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Alzheimer's disease\u2010associated P460L variant of EphA1 dysregulates receptor activity and blood\u2010brain barrier function"],"prefix":"10.1002","volume":"20","author":[{"given":"Helen A.","family":"Owens","sequence":"first","affiliation":[{"name":"Division of Infection and Immunity School of Medicine, Cardiff University  Cardiff UK"},{"name":"School of Dentistry Cardiff University  Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E.","family":"Thorburn","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity School of Medicine, Cardiff University  Cardiff UK"},{"name":"UK Dementia Research Institute, Cardiff University  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