TY - JOUR
KW - Alzheimer's disease
KW - Experimental models of disease
KW - induced pluripotent stem cells
KW - Neurodegeneration
KW - Neuroimmunology
AU - Julien Klimmt
AU - Carolina Cardoso Gonçalves
AU - Jessica Valentina Montgomery
AU - Stephan A. Müller
AU - Merle Bublitz
AU - Severin Filser
AU - Lars Paeger
AU - Brigitte Nuscher
AU - Angelika Dannert
AU - Sigrun Roeber
AU - Veronica Pravata
AU - Martina Schifferer
AU - Joshua J. Shrouder
AU - Nathalie Schulz
AU - Judit González-Gallego
AU - Silvia Cappello
AU - Thomas Misgeld
AU - Nikolaus Plesnila
AU - Eduardo Beltrán
AU - Jochen Herms
AU - Elena De Domenico
AU - Marc D. Beyer
AU - Joachim L. Schultze
AU - Christian Haass
AU - Stefan F. Lichtenthaler
AU - Caterina Carraro
AU - Dominik Paquet
AB - Stem-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.
BT - Nature Neuroscience
DA - 2026-08-04
DO - 10.1038/s41593-026-02367-0
LA - en
N2 - Stem-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.
PY - 2026
SP - 1
EP - 17
T2 - Nature Neuroscience
TI - A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes
UR - https://www.nature.com/articles/s41593-026-02367-0
Y2 - 2026-08-06
SN - 1546-1726
ER -