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

Microglia are central players in Alzheimer's disease pathology but analyzing microglial 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 App NL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric A beta oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2 R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer's disease 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 a multipronged response to Alzheimer's disease-related pathology, which should be taken into account in translational studies. Human microglia transplanted in the mouse brain mount a multipronged response to amyloid-beta pathology, displaying unique transcriptional states. Alzheimer's disease risk genes are differentially regulated across cell states and profoundly alter microglial function.