{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:06:27Z","timestamp":1775538387685,"version":"3.50.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Methamphetamine (METH), a psychostimulant, can cause the blood\u2013brain barrier (BBB) breakdown through astrocyte endfeet swelling and endothelial cell impairment. Our previous studies have shown that phosphorylated microtubule-associated protein Tau (p-Tau) levels increase, especially in neurons, after METH exposure. However, whether p-Tau accumulates in the endothelial cells of METH mouse brains remains unclear. The effects of endothelial p-Tau accumulation on BBB integrity in a chronic METH mouse model are elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The A\n                      <jats:sub>2A<\/jats:sub>\n                      R-GSK3\u03b2 signaling pathway protein levels were evaluated in chronic METH mice model. The BBB integrity, endothelial p-Tau level and behavioral performances were tested after A\n                      <jats:sub>2A<\/jats:sub>\n                      R inhibiton, GSK3\u03b2 inhibition or p-Tau knockout.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this study, we found that METH might induce the upregulation of adenosine receptor subtype 2A (A\n                      <jats:sub>2A<\/jats:sub>\n                      R), leading to glycogen synthase kinase-3 beta (GSK3\u03b2) activation and Tau phosphorylation in BBB endothelial cells. Chronic METH exposure induced BBB breakdown and anxiety- and depression-like behavioral abnormalities. Pharmacological inhibition of A\n                      <jats:sub>2A<\/jats:sub>\n                      R and GSK3\u03b2 activation alleviated p-Tau accumulation, mitigated the behavioral changes, and alleviated BBB destruction induced by METH. Moreover, genetically knocking out Tau also attenuated BBB destruction and behavioral changes induced by chronic METH.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Based on these findings, we propose an A\n                      <jats:sub>2A<\/jats:sub>\n                      R-GSK3\u03b2 signaling-dependent mechanism to elucidate METH-induced BBB breakdown. We suggest p-Tau as a promising candidate target to reduce BBB destruction and behavioral abnormalities in METH abusers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1801011","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T04:23:18Z","timestamp":1775535798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial adenosine A2A receptor activation-mediated Tau hyperphosphorylation leads to blood\u2013brain barrier breakdown in a chronic methamphetamine mouse model"],"prefix":"10.3389","volume":"13","author":[{"given":"Ying","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meigui","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, The Fourth People's Hospital of Guiyang City","place":["Guiyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xingxing","family":"Xie","sequence":"additional","affiliation":[{"name":"West China School of Pharmacy, Sichuan University","place":["Chengdu, China"]},{"name":"Department of Pharmacy, Ya'an People's Hospital","place":["Ya'an, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Ren","sequence":"additional","affiliation":[{"name":"Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaorong","family":"Huang","sequence":"additional","affiliation":[{"name":"Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shanshan","family":"Hu","sequence":"additional","affiliation":[{"name":"Good Clinical Practice Center, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1038\/npp.2013.307","article-title":"Methamphetamine causes degeneration of dopamine cell bodies and terminals of the nigrostriatal pathway evidenced by silver staining","volume":"39","author":"Ares-Santos","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"69","DOI":"10.3389\/fnins.2015.00069","article-title":"Methamphetamine effects on blood-brain barrier structure and function","volume":"9","author":"Northrop","year":"2015","journal-title":"Front 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