PT  - JOURNAL ARTICLE
AU  - Pranav Preman
AU  - Julia TCW
AU  - Sara Calafate
AU  - An Snellinx
AU  - Maria Alfonso-Triguero
AU  - Nikky Corthout
AU  - Sebastian Munck
AU  - Dietmar Rudolf Thal
AU  - Alison M Goate
AU  - Bart De Strooper
AU  - Amaia M Arranz
TI  - Human iPSC-derived astrocytes transplanted into the mouse brain display three morphological responses to amyloid-β plaques
AID  - 10.1101/2020.11.19.389023
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.19.389023
4099  - http://biorxiv.org/content/early/2020/11/20/2020.11.19.389023.short
4100  - http://biorxiv.org/content/early/2020/11/20/2020.11.19.389023.full
AB  - Background Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer’s disease comes from molecular studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.Methods To address these challenges, we established an approach to study human astroglia within the context of the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived glia progenitors into neonatal brains of immunodeficient mice.Results Xenografted (hiPSC)-derived glia progenitors differentiate into astrocytes that integrate functionally within the mouse host brain and mature in a cell-autonomous way retaining human-specific morphologies, unique features and physiological properties. In Alzheimer’s chimeric brains, transplanted hiPSC-derived astrocytes respond to the presence of amyloid plaques with various morphological changes that seem independent of the APOE allelic background.Conclusion In sum, this chimeric model has great potential to analyze the role of patient-derived and genetically modified astroglia in Alzheimer’s disease.Competing Interest StatementBDS is a consultant for Eisai. PP, JTCW, AS, SC, MAT, NC, SM, DRT, AMG and AMA declare that they have no competing interests.5 M5 months of ageADAlzheimer’s diseaseAβamyloid-βAPOEApolipoprotein ECDRclinical dementia ratingDIVdays in vitroEBembryoid bodiesGPCsglia progenitor cellshiPSCshuman induced pluripotent stem cellsIFimmunofluorescenceIVCindividually ventilated cagesNFTneurofibrillary tanglesNPCsneural progenitor cellsPAMprotospacer adjacent motifPMIpost-mortem intervalRFPred fluorescent proteinRTroom temperatureSPFspecific pathogen freessODNsingle-strand oligo-deoxynucleotideTzvThiazovivinWTWild-type