Fig. 2

Distinct subsets of genes in the hippocampus are affected by C5ar1 knockout or C5a overexpression. A Schematic diagram of experimental design highlighting 372 RNA-seq samples processed from cortices and hippocampi of 6 mouse genotypes during disease progression at 2.7, 5, 7, and 10 months of age. B UMAP embedding representation of 372 RNA-seq samples represented in A. Samples separated out mostly by tissue type (hippocampus (HP) and cortex (CX)). Samples from WT mice are represented in shades of blue, from the C5ar1KO cohort in shades of gray, from the C5aGFAP cohort in shades of yellow, from the Arctic cohort in shades of orange, from the ArcC5ar1KO cohort in shades of green, and samples from the ArcC5aGFAP cohort in shades of pink. C Heatmap of 1763 genes with dynamic temporal profiles in the hippocampus identified by maSigPro clustering (alpha < 0.05, FDR < 0.05%). Each column represents the average expression for a time point and each row represents a gene. Each cluster represents a subset of genes that show a similar pattern of expression along the time-course in the hippocampus. Clusters shown in brown gradient and lilac gradient (far left) represent genes whose expression changes are driven by C5ar1KO or C5a overexpression, respectively. RNA-seq data (TPM) is row-mean normalized. Astrocyte-associated genes (Ast), genes upregulated in microglia isolated from Arctic mice (Arc Mic), and genes upregulated with pathology progression in the 5xFAD mice (5xFAD Up) present in each cluster are shown (far right). D Heatmap of 15 genes of the complement pathway expressed in hippocampal samples that were present in maSigPro identified clusters. RNA-seq data (TPM) is row-mean normalized. E Representative diagram of the Classical pathway activation of the complement cascade, highlighting complement-associated genes present in the maSigPro identified clusters (as seen in panel D). N = 4–10 mice/genotype/age