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Rather than stabilizing microtubules, tau promotes labile microtubule domains, redefining its role in neurodegeneration and underscoring the need for human models that capture temporal disease progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Human induced pluripotent stem cells carrying\n                      <jats:italic>MAPT<\/jats:italic>\n                      <jats:sup>WT\/P301L<\/jats:sup>\n                      ,\n                      <jats:italic>MAPT<\/jats:italic>\n                      <jats:sup>WT\/P301S<\/jats:sup>\n                      , or\n                      <jats:italic>MAPT<\/jats:italic>\n                      <jats:sup>WT\/R406W<\/jats:sup>\n                      mutations and isogenic controls were differentiated into forebrain cortical organoids (1 to 8 months). Tau isoforms, microtubule dynamics, MAP6 regulation, neuronal activity, tau mRNA stability, and tau pathology were analyzed using biochemical, imaging, and electrophysiological approaches, some of which were benchmarked to\n                      <jats:italic>postmortem<\/jats:italic>\n                      behavorial variant FTD cortex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Early\u2010phase tau mutant organoids showed elevated tau, hyperdynamic microtubules, and neuronal hyperexcitability, partially reversible by tau reduction. Late\u2010phase organoids exhibited insoluble tau accumulation, microtubule hyperstability, and neurodegeneration and reactive astrocytes, accompanied by opposing, phase\u2010dependent MAP6 changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>This work reveals a biphasic tau\u2010MAP6\u2010microtubule mechanism driving tauopathy and establishes these organoids as a platform for phase\u2010specific therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71565","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:00:45Z","timestamp":1783422045000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patient\u2010derived forebrain cortical organoids reveal biphasic tau\u2013MAP6\u2013microtubule axis dysfunction in tauopathy"],"prefix":"10.1002","volume":"22","author":[{"given":"Xiaohuan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skandha","family":"Ramakrishnan","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor C.","family":"Ogbolu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas M.","family":"Kanaan","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience Michigan State University  Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste M.","family":"Karch","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Knight Alzheimer Disease Research Center Washington University in St Louis  St Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Baas","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Qiang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania 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