Extended Data Fig. 7: Disease-associated microglial (DAM) signature in 5XFAD;Trem1+/- mice.
a PCA of significantly regulated DAM signature genes from primary microglia isolated from WT, 5XFAD and 5XFAD/Trem1+/- mice. Individual microglial samples were pooled from 2 male mice (n = 3 samples per condition). b Hierarchical clustering of DAM signature gene set showing homeostatic, DAM Stage 1 and DAM Stage 2 genes. Scale represents z-score values from FPKM. c Hierarchical clustering of top 170 DEGs (FDR-corrected) belonging to the full DAM signature gene set. Scale represents z-score values from FPKM. Scale represents z-score values from FPKM. d (Left) Percent of CX3CR1+ microglia in young (3 mo) and 13–17 mo WT, 5xFAD and 5xFAD;Trem1+/- mice. (Right) MFI of CX3CR1+ microglia. One-way ANOVA with Tukey’s multiple comparison, not significant (n = 5–8 male and female mice per group as shown). e (Left) Percent of Tmem119+ microglia in young (3 mo) and 13–17 mo WT, 5xFAD and 5xFAD;Trem1+/- mice. (Right) MFI of Tmem119+ microglia. One-way ANOVA with Tukey’s multiple comparisons (n = 4-5 mice per group). f (Left) Total time exploring (in seconds) during the training phase of the NOR task in APPSwe mice; ANOVA with Tukey’s post-hoc test (n = 14-17 male and female mice per condition as shown). g Motor speed (pixels/sec) during the final training session of the Barnes maze; ANOVA with Tukey’s post-hoc test (n = 6 male and female mice per group). h Distance traveled during the final training session of the Barnes maze; ANOVA with Tukey’s post-hoc test (n = 6 male and female mice per group). i Coupling assay tracings of synaptic mitochondria oxygen consumption rates (OCR). Shown over time are the rates of basal Complex II respiration, State III (ADP stimulated respiration), State IV (oligomycin) and State IIIu (State III uncoupled, FCCP) that were consecutively measured over the course of the assay (n = 5-9 male mice per condition). j Diagram of model of action of TREM1 in aging and transgenic mice with amyloid accumulation. In aging, peripheral TREM1 activity contributes to declines in myeloid metabolism and immune functions that lead to age-dependent cognitive decline. In models of amyloid accumulation, both peripheral and microglial TREM1 contribute to cognitive deficits associated with local accumulation of amyloid.
