Background: 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.
Method: To circumvent these issues, here we collected 138,577 single cell expression profiles of human stem cell derived-microglia from a xenotransplantation model of AD.
Result: 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 Aβo. Expression of AD risk genes is distributed over this multi-pronged response to amyloid pathology. Genetic deletion of TREM2 or APOE, as well as APOE polymorphisms and TREM2 expression in the transplanted microglia modulate these responses differentially.
Conclusion: We have identified multiple transcriptomic cell states adopted by microglia in response to AD-related pathology, which should be taken into account in translational studies.
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