Extended Data Fig. 1: Bumetanide is also predicted to rescue the transcriptomic signature of aging in apoE4-KI mouse cortex.
a, PCA plot of top 500 variable genes in apoE4-KI mouse cortex shows a distinct effect of age, with 3 month-old brains grouping separately from 12 and 24 month-old brains. b, Venn diagrams of the overlapping DE genes (logFC > 2, unadjusted P < 0.05 by Wald test with default parameters (DESeq2 v 1.30.2)) and DE pathways (unadjusted P < 0.05 by bespoke enrichment method, kegga function (limma v 3.36.5)) between 12 vs 3 month-old apoE4-KI brains and 24 vs 3 month-old apoE4-KI brains. c, Graphs of compounds ordered by CMap score against DE genes (logFC > 2, unadjusted P < 0.05 by Wald test with default parameters (DESeq2 v 1.30.2)) in 12 vs 3 month-old apoE4-KI brains (see Methods for details). Bumetanide has a negative CMap score in the 7th percentile of all drugs in the CMap. d, Graphs of compounds ordered by CMap score against DE genes (logFC > 2, unadjusted P < 0.05 by Wald test with default parameters (DESeq2 v 1.30.2)) in 24 vs 3 month-old apoE4-KI brains. Bumetanide has a negative CMap score in the 8th percentile of all drugs in the CMap. e, Histogram of the rank of FC of the DE genes (logFC > 2, unadjusted P < 0.05 by Wald test with default parameters (DESeq2 v 1.30.2)) in 12 vs 3 month-old apoE4-KI brains, which were also measured in the CMap database after bumetanide treatment. The mean rank of all genes in this gene set is denoted by the black line, the average mean FC rank of up-regulated genes (colored red in histogram) is denoted by the dashed red line and the mean FC rank of the down-regulated genes (colored blue in histogram) is denoted by the blue dashed line. P-value of significance of the “flip” of up- and down-regulated FC rank means away from the rank mean of all genes as calculated by Monte-Carlo simulation is shown (P = 0.056). This p-value does not reach significance even while the magnitude of the “flip” is quite large. f, Histogram of the rank of FC of the DE genes (logFC > 2, unadjusted p-value < 0.05 by Wald test with default parameters (DESeq2 v 1.30.2)) in 24 vs 3 month-old apoE4-KI brains which were also measured in the CMap database after bumetanide treatment. The mean rank of all genes in this gene set is denoted by the black line, the average mean FC rank of up-regulated genes (colored red in histogram) is denoted by the dashed red line and the mean FC rank of the down-regulated genes (colored blue in histogram) is denoted by the blue dashed line. P-value of significance of the “flip” of up- and down-regulated FC rank means away from the rank mean of all genes as calculated by Monte-Carlo simulation is shown (P = 0.064). This p-value does not reach significance even while the magnitude of the “flip” is quite large.
