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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,10,21]]},"abstract":"<jats:p>\n                    Patient-specific, human-based cellular models integrating a biomimetic blood\u2013brain barrier, immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. To construct a human cell-based model that includes these features and all six major brain cell types needed to mimic disease and dissect pathological mechanisms, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model by engineering a brain-inspired 3D hydrogel and identifying conditions to coculture these six brain cell types, all differentiated from patient induced pluripotent stem cells. miBrains recapitulate in vivo\n                    <jats:italic toggle=\"yes\">\u2013<\/jats:italic>\n                    like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer\u2019s Disease pathologies associated with\n                    <jats:italic toggle=\"yes\">APOE4<\/jats:italic>\n                    genetic risk.\n                    <jats:italic toggle=\"yes\">APOE4<\/jats:italic>\n                    miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic glial fibrillary acidic protein. Unlike the coemergent fate specification of glia and neurons in other organoid approaches, miBrains integrate independently differentiated cell types, a feature we harnessed to identify that\n                    <jats:italic toggle=\"yes\">APOE4<\/jats:italic>\n                    in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2511596122","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:47:41Z","timestamp":1760723261000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":40,"title":["Engineered 3D immuno-glial-neurovascular human miBrain model"],"prefix":"10.1073","volume":"122","author":[{"given":"Alice E.","family":"Stanton","sequence":"first","affiliation":[{"name":"Koch Institute, Massachusetts Institute of 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