A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases

Recent studies highlight the critical role of microglia in neurodegenerative disorders and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. We developed the hCSF1Bdes mouse line, which is suitable as a new transplantation model and available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additionally, we crossed this model with two humanized App KI mice, the AppHu and the AppSAA. Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimer's disease. Our results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore, we confirmed the multipronged response of microglia in the context of Alzheimer's disease. The hCSF1Bdes and the crosses with the Alzheimer's disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community. The hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease. Overall design: RNAseq profiling of flow cytometry-sorted human H9-embryonic stem cell-derived microglia (CD11b positive/human CD45 positive) xenotransplanted in the AppSAA mouse model of Alzheimer's disease and the control AppHu mouse model and harvested at 6 months of age