Fig. 5
In vivo reversion of AD signatures. a Scheme of drug treatments and evaluation b Novel object recognition (NOR) test of 6-month-old animals. Appwt (circles; light blue) and AppNL-F (squares; dark blue) mice were treated for 4 weeks with the indicated drugs. Mean ± SD of the % of time exploring the novel object is shown (n = 4–7). One-sample t-test vs. a hypothetical value of 50 (* p value < 0.05). Red points indicate the animals selected for RNAseq analysis. c Signature reversion. In the X-axis, genes are ranked by their differential expression in the comparison of drug- vs. vehicle-treated AppNL-G-F mice. The Y-axis represents the running Enrichment Score (ES) performed for the AD signatures (AD-UP, blue; AD-DW, red) that were reverted upon treatment. Dashed vertical lines indicate the point at which the ES reaches its maximum deviation from zero, defining the leading-edge subset of genes that contribute the most to the enrichment result. The observed ES is compared to a null distribution of 10,000 randomized signatures of the same size (95% CI shown as a shaded gray area). For example, AD-DW signature genes (red line) tend to be ranked among the 5000 most upregulated genes in response to penbutolol treatment (second panel), with an ES of 0.63, which is significantly higher than that of random signatures of the same size (p value < 0.0001). This is interpreted as a significant signature reversion. RNAseq data were obtained from n = 4 mice per condition. d Heatmaps showing the reversion rank of the top-40 genes belonging to the leading-edge of the AD-UP signature (blue; left panel) and AD-DW signature (red; right panel) in two or more treatments, sorted by the average row value. Data obtained from n = 4 mice per condition. e Leading-edge genes of the AD-UP and AD-DW signatures reverted by the different treatments. We show a few genes in the AD signatures that are up- (red) or down- (blue) regulated (t-score) in the vehicle-treated AppNL-G-F mice compared with vehicle-treated Appwt animals (bold dots) or in the drug-treated AppNL-G-F mice compared with vehicle-treated Appwt animals (empty dots). RNAseq data were obtained from n = 4 mice per condition