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While genomic studies have tentatively linked\n                    <jats:italic>RBFOX1<\/jats:italic>\n                    to AD susceptibility, its functional synergy with\n                    <jats:italic>APOE4<\/jats:italic>\n                    has never been experimentally defined. We engineered\n                    <jats:italic>APOE3<\/jats:italic>\n                    or\n                    <jats:italic>APOE4<\/jats:italic>\n                    isogenic human cerebral organoids with CRISPR\/Cas9\u2010mediated\n                    <jats:italic>RBFOX1<\/jats:italic>\n                    knockout. Remarkably,\n                    <jats:italic>RBFOX1<\/jats:italic>\n                    depletion selectively triggered robust microglial generation exclusively in\n                    <jats:italic>APOE4<\/jats:italic>\n                    organoids. Time\u2010course gene expression revealed that this APOE4\u2010specific effect correlated with prolonged mesodermal priming during early embryoid body differentiation, creating a permissive niche for microglial lineage specification. The emergent microglia exhibited pronounced neurotoxic phenotypes, including pro\u2010inflammatory factor secretion, synaptic architecture remodeling, and lipid droplet accumulation in organoids. These changes coincided with aggravated Tau hyperphosphorylation and electrophysiological abnormalities, collectively mirroring multifaceted AD pathology. Our findings establish RBFOX1 as a potential AD protective factor, a critical suppressor of APOE4\u2010glia crosstalk, and demonstrate that its loss unleashes a microglia\u2010mediated neurodegenerative cascade. By developing cerebral organoids with autonomous microglial networks, we present a platform capable of modeling genotype\u2010dependent neuron\u2010glia interactions in AD, opening new avenues for mechanistic and therapeutic exploration.\n                  <\/jats:p>","DOI":"10.1002\/exp2.70160","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T04:11:09Z","timestamp":1775189469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<i>RBFOX1<\/i>\n                    Dysfunction Unlocks\n                    <i>APOE4<\/i>\n                    \u2010Associated Microglial Genesis and Exacerbates Alzheimer's Pathology in Human Cerebral Organoids"],"prefix":"10.1002","volume":"6","author":[{"given":"Bowen","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute For Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East 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