biostudies-literatureMancuso RAlzheimer’s AssociationEuropean Research CouncilMedical Research CouncilUniversiteit AntwerpenFonds Wetenschappelijk OnderzoekEC | Horizon 2020 Framework ProgrammeAlzheimer's Association886-900https://www.ebi.ac.uk/biostudies/studies/S-EPMC11089003biostudies-literatureUnknown27(5)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 reNature neuroscienceXenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology.PMC11089003MR/Y014847/1834682FFB210307CELLPHASE_ADG0K9422NXenoMicrogliaADAARF-20-684397G0C9219N12ZX621N1139520N1122423NBalusu SDe Strooper BMartinez-Muriana APremereur JVerfaillie CWolfs LPreman PVan Den Daele JBijnens BPoovathingal SMancuso RFiers MDavis EFattorelli NGeric IPolanco PSerneels LfalseXenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β 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 re2024-01-01T00:00:00Z2024 May2026-06-01T20:23:58.725Z2026-05-20T03:07:57.245ZS-EPMC110890033853901510.1038/s41593-024-01600-y