Fig. 5
Comparison of transcriptional profiles between ASO mediated APOE and TREM2 knockdown with full APOE-KO and TREM2-KO human microglia. A,C,E Gene set enrichment analysis (GSEA): Pre-ranked enrichment scores of the microglial subtype marker gene sets under knockout and ASO treatment. Each point represents the GSEA Normalised Enrichment Score of the gene set (top 50 marker genes of the labelled microglial subtype) against the full list of genes ranked by the log-fold change when comparing the ASO treatment group against the vehicle group (x-axis) and the knockout group against the control group (y-axis). Significant GSEA enrichment is denoted by FWER < 0.05. B Scaled log fold changes in gene expression between APOE knockout and control A-lines (y-axis), and APOE ASO-1 treatment and the vehicle at 1 week (x-axis) of the top 50 marker genes from each microglial subtype. D Scaled log fold changes in gene expression between APOE knockout and control C-lines (y-axis), and APOE ASO-1 treatment and the vehicle at 1 week (x-axis) of the top 50 marker genes from each microglial subtype (F) Scaled log fold changes in gene expression between TREM2 knockout and control (y-axis), and TREM2 ASO-171 treatment and the vehicle at 1 week (x-axis) of the top 50 marker genes from each microglial subtype. Since the Knockout experiment and the ASO treatment experiments were performed under different experimental conditions, the Log2fold change of each DE analysis was scaled to -1 and 0 for LFC < 0 and 0 to 1 for LFC > 0. All analysis were performed on xenotransplanted microglia isolated from 6–7-month-old AppNL−G−F mice. G Expression of microglia homeostatic markers, P2RY12, TMEM119 and CX3CR1 in human microglia isolated from 10–12-week-old xenotrasplanted mice 7 days after administration of 125ug MALAT1 targeting ASO compared to vehicle treated mice. CNRQ = Calibrated Normalized Relative Quantities. Bars represent mean ± SEM, n = 5–7/group. Statistical differences based on the Mann–Whitney test: *p < 0.05