Fig. 9
Microglia have differential responses to plaque and tau pathology. a-g Comprehensive analysis of all microglia (i.e., disease-associated and homeostatic) across both 5xFAD and PS19 cohorts. a UMAP of 41,790 microglia merged and integrated across both 5xFAD;ApoeCh and PS19;ApoeCh datasets (n = 3 for 5xFAD;ApoeCh, 5xFAD, PS19;ApoeCh, and PS19; n = 5 for ApoeCh; n = 6 for WT). Cells are labelled using their annotations from original datasets prior to merging. b UMAP of merged microglia split by genotype. DAMs in PS19 genotype are localized to one side of the DAM cluster in UMAP space. c Feature plots of DAM markers Cd74, H2-Ab1, H2-Aa, Trem2, Cst7, and Apoe in all microglia. d Distribution of DAMs and homeostatic microglia across genotypes. (d., Upper) Average microglial cell counts per section across each of the six genotypes. Cell counts for each genotype were divided by the total number of samples in that genotype. (d., Lower) Proportion of the number of cells in each genotype, grouped by DAM versus homeostatic microglia. e Scatterplot of the average difference in all microglia for all significant genes (i.e., padj < 0.05) between 5xFAD vs. WT and PS19 vs. WT comparisons. Directly correlated genes (blue) occur in the same direction for both comparisons, while inversely correlated genes (orange) occur in opposite directions for each comparison. Linear regression line showing the relationship between the two comparisons plotted in blue. f Scatterplot of the average difference in all microglia for all significant genes between 5xFAD;ApoeCh vs. 5xFAD and PS19;ApoeCh vs. PS19. g Volcano plot of DEGs between 5xFAD and PS19 DAMs. h–k Comparison of mouse single-cell spatial transcriptomics with human snRNA-seq data. h Schematic of data processing for snRNA-seq. Frontal cortex samples from the PSEN1-E280A heterozygous;APOE3Ch homozygous individual (n = 1) and PSEN1-E280A heterozygote controls (n = 5) were first reduced to 975 genes that overlapped with the CosMx mouse neuroscience panel, then processed through the standard Seurat pipeline with SCTransform. The two datasets were then merged and integrated using reciprocal PCA to account for batch effects between runs for a resulting dataset of 13,643 cells. i UMAP of integrated snRNA-seq data, with microglia highlighted. j DEGs between PSEN1-E280A;APOE3Ch vs. PSEN1-E280A in all microglia. Genes with padj < 0.05 are colored red (upregulated) or blue (downregulated). k Venn diagram of positively correlated genes between three comparisons: PSEN1-E280A;APOE3Ch vs. PSEN1-E280A (yellow oval), 5xFAD;ApoeCh vs. 5xFAD (blue oval), and PS19;ApoeCh vs. PS19 (green oval). Genes were considered positively correlated if the log-twofold-change of the average expression between the two groups was the same sign for both comparisons, and if the adjusted p-value was less than 0.05 for both comparisons. Upregulated genes are written in red text, while downregulated genes are written in blue text