Figure 2.

An interferon response-associated gene module is present along a distinct microglial activation trajectory upregulated in aged mice and mice with amyloid pathology. (A) The genetic network containing Oas1a from microglial cells isolated from wild-type and APP^NL-G-F knock-in mice at 3, 6, 12 and 21 months of age analysed by scRNA-seq.⁹ The 50 genes showing the highest connectivity are plotted, and Oas1a is highlighted with a black oval. Green nodes represent genes, edge lines represent co-expression connections, and the central large red nodes are the hub genes (the full network given in Supplementary Table 4). (B) Semi-supervised pseudotime ordering of microglial cells isolated from wild-type and APP^NL-G-F knock-in mice based on expression,⁹ with Monocle 2, shows homeostatic cells as the root state, and ARM and IRM as the end points of distinct activation trajectories. (C) The gene module containing Oas1a is upregulated (yellow data-points) along the IRM-associated activation trajectory. The expression of this module is relatively absent from both the root homeostatic state and the ARM trajectory (purple data-points). (D) Mean normalized expression of the 60 most central genes in the interferon-response module is greater in microglia isolated from aged wild-type relative to young adult mice (6–8 weeks versus 16–18 months of age; n = 6 mice per group). Data are shown as mean ± SEM. Student’s t-test; **P < 0.01. Further analysis of data from O’Neil et al.⁶⁹ (E) Mean normalized expression of the 60 most central genes in the interferon-response module is greater in microglia isolated from PSEN2/APP relative to wild-type mice at 14–15 months of age (n = 6–9 mice per group). Data are shown as mean ± SEM. Student’s t-test; ****P < 0.0001. Further analysis of data from Friedman et al.¹³