General Information about the Dataset

Abstract

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 App^NL-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 Aβo. 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 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 a multipronged response to AD-related pathology, which should be taken into account in translational studies.

Experimental Setting:

Transcriptional landscape of xenotransplanted microglia (6 months)

• hESC/hiPSC-derived microglia transplanted in App^hu/hu and App^NL-G-F
• hESC: H9
• iPSCs: C- and A-lines

Response to progressive amyloid pathology deposition (3 & 6 months)

• 3 isogenic iPSC-C lines transplanted in App^NL-G-F and isolated at 2 stages of patholgy

Response in absence of plaques and ablating the APOE-TREM2 microglial axis (6 months)

• H9, iPSC-C and iPSC-A cells transplanted in App^NL-G-F and App^NL-G-F Apoe^KO
• APOE^3/3 and APOE^KO cells (iPSC-C and iPSC-A lines) transplanted in App^NL-G-F
• H9 and H9-TREM2^KO cells transplanted in App^NL-G-F

Response to soluble amyloid species (3 months)

• iPSC-C and iPSC-A cells (3 isogenic lines each) transplanted in App^hu/hu and acutely injected with soluble amyloid-beta aggregates for 6h

Response to genetic mutations (6 months)

• APOE^2/2 , APOE^3/3 , APOE^4/4 cells (iPSC-C and iPSC-A lines) transplanted in App^NL-G-F
• H9 , H9-TREM2^KO , H9-TREM2^R47H , cells transplanted in App^NL-G-F

Integration with snRNAseq human AD datasets

• Gerrits et al. (Boddeke lab)
• Sayed et al. (Li Gan lab)
• Zhou et al. (Colonna lab)
• Olah et al. (De Jager lab)
• Sun et al. (Kellis and Tsai labs)

Computational Info:

• DNA library prep: CG000204 Chromium Next GEM Single Cell 3’ Reagent Kits v3.1
• The raw FastQ files were aligned by Cellranger (v.3.1.0) against the human genome database (hg19, Ensembl 87).

Publication

More Information can be found in the: Xenografted human microglia display diverse transcriptomic states in response to Alzheimer’s disease-related Aβ pathology