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

BackgroundRecent 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. MethodsWe developed the hCSF1Bdes mouse line suitable as new transplantation model 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. Additional 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 Alzheimers disease. ResultsOur 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 Alzheimers disease. The hCSF1Bdes and the crosses with the Alzheimers 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. Conclusionthe 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.