02842nas a2200517   4500000000100000000000100001008004100002260001500043653002400058653003500082653003500117653002200152653002000174100001800194700003200212700003300244700002300277700001800300700001900318700001600337700002100353700002100374700001800395700002100413700002300434700002300457700002000480700002800500700002000528700001900548700002200567700002100589700001700610700002200627700001800649700002400667700002000691700002800711700002100739700001900760245013800779856005500917300000900972520132900981022001402310       2026                            d  c2026-08-0410aAlzheimer's disease10aExperimental models of disease10ainduced pluripotent stem cells10aNeurodegeneration10aNeuroimmunology1 aJulien Klimmt1 aCarolina Cardoso Gonçalves1 aJessica Valentina Montgomery1 aStephan A. Müller1 aMerle Bublitz1 aSeverin Filser1 aLars Paeger1 aBrigitte Nuscher1 aAngelika Dannert1 aSigrun Roeber1 aVeronica Pravata1 aMartina Schifferer1 aJoshua J. Shrouder1 aNathalie Schulz1 aJudit González-Gallego1 aSilvia Cappello1 aThomas Misgeld1 aNikolaus Plesnila1 aEduardo Beltrán1 aJochen Herms1 aElena De Domenico1 aMarc D. Beyer1 aJoachim L. Schultze1 aChristian Haass1 aStefan F. Lichtenthaler1 aCaterina Carraro1 aDominik Paquet00aA reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes  uhttps://www.nature.com/articles/s41593-026-02367-0  a1-173 aStem-cell-based in vitro models offer promising potential to elucidate human brain cell functions and interactions, but limitations in reproducibility, maturation and cell-type diversity persist. Especially, prolonged incorporation of mature microglia and studies of neuroinflammation have proven challenging. Here, we developed a human induced pluripotent stem cell-based three-dimensional cortical brain tissue model (3BTM) containing neurons, astrocytes and microglia with high reproducibility, maturity and viability. 3BTMs show morphological, functional and proteomic maturation of all cell types, leading to high similarity to their in vivo counterparts. Incorporated microglia survive for over 6 months and display mature morphology, functions and gene expression. Importantly, when engineered to model Alzheimer’s disease pathology, 3BTMs recapitulate key disease hallmarks, including amyloid deposition, increased phospho-tau levels and neuroinflammation, with microglia shifting their transcriptional landscape to disease-relevant signatures. Treatment of Alzheimer’s disease 3BTMs with anti-Aβ immunotherapy cleared deposits and largely reversed disease signatures in glia. Together, our microglia-containing model provides a platform for studying physiological and pathological states of human brain tissue.  a1546-1726