Fig. 4: Activating Nrf2 in models of tauopathy and ß-amyloidopathy. | Nature Communications

Fig. 4: Activating Nrf2 in models of tauopathy and ß-amyloidopathy.

From: Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

Fig. 4

A Enrichment analysis of genes induced in MAPTP301S and APP/PS1 mice for transcription factor (TF) targets performed in Enrichr23 (upper) and TFEA.ChiP24 (lower). B RNA-seq analysis of astrocytes sorted from GFAP-Nrf2 mice, vs. WT (n = 5). Genes induced (red) and repressed (blue) are highlighted (>1FPKM, Benjamini–Hochberg-adjusted p value (p_adj) <0.05). C (Left). Enrichment of genes induced in GFAP-Nrf2 astrocytes for genes induced in MAPTP301S astrocytes (Fig. 1C), APP/PS1 astrocytes (Fig. 1H), and in both (Fig. 3A), and for genes induced in human AD astrocytes7. *p values: 4.23E−11, 4.1E−21, 8.48E−15, 0.0001 (Fisher’s exact test). #p values: 0.0008, 0.013 (normal approximation to difference in log odds ratios). (Right) Enrichment of genes induced in GFAP-Nrf2 astrocytes for gene sets in Supplementary Fig. 2A–C. *p values: 8.7E−07, 4.0E−05, 0.007 (Fisher’s exact test). qPCR analysis of the indicated genes in MAPTP301S and APP/PS1 astrocyte translatome. Two-way ANOVA for genotype effect: F (1,53) = 23.29, p = 1.2E−05 (D); F (1,55) = 46.13, p = 8.3E−09 (E) (n = 4). F Illustrating our crossing strategy. G Expression of selected Nrf2 target genes in the cortex (from RNA-seq). *p_adj: 1.7E−178, 2.5E−119, 9.4E−45, 2.3E−64, 3.9E−59, 4.1E−54, 8.6671E−61, 2.52E−22, 1.2E−14, 2.6E−15, 7.3E−11, 1.2E−11. H Analysis repeated on hippocampal tissue. *p_adj: 4.3E−31, 3.9E−27, 2.3E−12, 1.9E−07, 8.3E−07, 0.0018, 1.6E−33, 5.7E−45, 4.1E−14, 1.6E−06, 8.9E−10, 6.1E−10; adjusted p values (hippocampus): 3.8E−11, 8.2E−14, 1.0E−06, 3.2E−08, 0.0012, 1.03E−05, 0.049, 7.5E−09, 1.6E−11, 2.9E−08, 1.6E−09, 0.049, 0.007 (n = 3). I, J Western analysis of cortical and hippocampal Nqo1 and Gclm. Two-way ANOVA for cortical Gclm: F (1, 8) = 98.68, p = 8.9E−06 (APP/PS1 effect); F (1, 8) = 493.2; p = 1.79E−08 (GFAP-Nrf2 effect); two-way ANOVA for cortical Nqo1: F (1, 8) = 69.4, p = 3.3E−05 (APP/PS1 effect); F (1, 8) = 773.2 p = 3.0E−09 (GFAP-Nrf2 effect). Two-way ANOVA for hippocampal Gclm: F (1, 8) = 26.67, p = 0.0009 (APP/PS1 effect); F (1, 8) = 91.36, p = 1.2E−05 (GFAP-Nrf2 effect); 2-way ANOVA for hippocampal Nqo1: F (1, 8) = 59.51, p = 5.7E−05 (APP/PS1 effect); F (1, 8) = 219.1, p = 4.3E−07 (GFAP-Nrf2 effect), n = 3 mice. *p values for GFAP-Nrf2 effect: 1.4E−06, 9.8E−06, 3.7E−08, 3.8E−04, 0.0025, 1.0E−06, 4.9E−08 (Bonferroni’s post-hoc test). #p values for APP/PS1 effect: 5.3E−06, 4.4E−06, 2.6E−05, 0.0011.

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