Fig. 8: Chlorpromazine prevents hyperimmune response and cognitive decline in Psen2N141I/+ mice. | Nature Communications

Fig. 8: Chlorpromazine prevents hyperimmune response and cognitive decline in Psen2N141I/+ mice.

From: Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα

Fig. 8

a, b Chlorpromazine (CPZ, 0.5 μM) treatment reduces the secretion (a; n = 6) and mRNA level (b; n = 4) of IL-6 in KI/+ microglia-treated with LPS for 12 h (LPS-treated WT vs LPS-treated KI/+: ###p < 0.0001 and ##p = 0.0019; LPS-treated WT vs LPS and CPZ-treated KI/+: †††p = 0.0002 and †††p < 0.0001; one-way ANOVA). c, d CPZ treatment restores Nr1d1 transcript (c; n = 3) and protein levels (d; n = 3) in KI/+ microglia-treated with LPS for 12 h (untreated WT vs untreated KI/+: ###p < 0.0001 and ##p = 0.0029; untreated WT vs CPZ-treated KI/+: †††p < 0.0001 and †p = 0.0214; one-way ANOVA). mRNA levels were normalized to Actb. e CPZ treatment reduces secretion of IL-6, CXCL1, CCL2, CCL5, and TNF-α in KI/+ microglia treated with fAβ42 (4 μM) for 24 h (n = 4) (fAβ42-treated WT vs fAβ42-treated KI/+: ###p = 0.0009, ###p = 0.0002, ###p < 0.0001, and ###p = 0.0001; fAβ42-treated KI/+ vs fAβ42 and CPZ-treated KI/+: ††p = 0.0077, †p = 0.0144, ††p = 0.0032, and †p = 0.0217; one-way ANOVA). CPZ was treated 30 min prior to LPS (a–e). f Schematic illustration of the experimental schedule. WT and KI/+ mice were analyzed 20 h after i.p. injection of LPS (0.35 μg/kg). CPZ (0.25 mg/kg) was administered i.p. 4 h prior to LPS injection. g ELISA of IL-6, CXCL1, CCL2, CCL5, and TNF-α in blood serum from WT and KI/+ mice (8-week-old, male, n = 7 mice per group) (LPS-injected WT vs LPS-injected KI/+: ###p < 0.0001; LPS-injected KI/+ vs LPS and CPZ-injected KI/+: †††p < 0.0001; one-way ANOVA). h, i Y-maze test with WT and KI/+ mice (8-week-old, male, n = 10 mice for LPS and CPZ-injected group; n = 7 mice for other groups) with arm alternation (h) and number of arm entries (i) (KI/+ vs LPS-injected KI/+: †††p < 0.0001; LPS-injected KI/+ vs LPS and CPZ-injected KI/+: †††p < 0.0001; one-way ANOVA). The bounds of the box represent 25th to 75th percentiles ranges. The center lines with the box represent the mean value and whiskers represent the minimum to the maximum range. Data are mean ± SEM. †p < 0.05, ††p < 0.01, and †††p < 0.001 vs untreated KI/+ control. ##p < 0.01, and ###p < 0.001 for the indicated comparisons. Source data are provided as a Source Data file.

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