Journal Article

DZNE-2026-00922

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A reproducible three-dimensional model of human brain tissue to investigate physiological and disease-associated microglia phenotypes.

Klimmt, J. ; Cardoso Gonçalves, C. ; Montgomery, J. V.DZNE* ; Müller, S. A.DZNE* ; Bublitz, M. ; Filser, S.Extern* ; Paeger, L.DZNE* ; Nuscher, B. ; Dannert, A. ; Roeber, S. ; Pravatà, M. V. ; Schifferer, M.DZNE* ; Shrouder, J. J. ; Schulz, N. ; González-Gallego, J. ; Cappello, S. ; Misgeld, T.DZNE* ; Plesnila, N. ; Beltrán, E. ; Herms, J.DZNE* ; De Domenico, E.DZNE* ; Beyer, M. D.DZNE* ; Schultze, J. L.DZNE* ; Haass, C.DZNE* ; Lichtenthaler, S. F.DZNE* ; Carraro, C.DZNE* ; Paquet, D.

2026
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/s41593-026-02367-0

Abstract: 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.

Keyword(s): Humans (MeSH) ; Microglia: physiology (MeSH) ; Microglia: pathology (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Brain: physiology (MeSH) ; Brain: pathology (MeSH) ; Induced Pluripotent Stem Cells: physiology (MeSH) ; Phenotype (MeSH) ; Neurons: physiology (MeSH) ; Astrocytes: physiology (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
2. Neuroproteomics (AG Lichtenthaler)
3. Translational Brain Research (AG Herms)
4. Neuronal Cell Biology (AG Misgeld)
5. Immunogenomics and Neurodegeneration (AG Beyer)
6. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)
3. 351 - Brain Function (POF4-351) (POF4-351)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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