Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related Aß pathology

Microglia are central players in Alzheimer's Disease (AD) pathology, but analyzing microglia states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the AppNL-G-F model of amyloid pathology and wild type controls. Xenografted human microglia adopt a disease-associated (DAM) profile similar to that seen in mouse microglia, but display a more pronounced HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine CRM response to oligomeric Aßo. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2R47H expression in the transplanted microglia modulate these responses differentially. The expression of other AD risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in response to AD-related pathology, which should be taken into account in translational studies. Overall design: The main goal of this project is to decipher the complex human microglial response towards amyloid aggregates. Here, we transplanted human microglia progenitors from several stem cell lines (UKBIO11-A, BIONi010-C and H9) into the mouse brain of AppNL-G-F, Apphu/hu or AppNL-G-F ApoE-/- mice to mimic several amyloid pathology conditions, including injection of oligomeric Aßo. After exposure to diseased conditions, we isolated human microglia and sequenced more than 138,000 microglia across 106 mice.