Figure 1.

PKR knockout modulates cognition and Aβ formation. (a–c) Behavior was studied in 9‐month‐old male and female wild‐type (n = 17), 5xFAD (n = 14), PKRKO (n = 14), and 5xFAD × PKRKO (double mutant, DM, n = 10) mice. (a) In the novel object location test, the percentages of time exploring the displaced object (new location, NL, 24 hr after first exposure) and the unmoved object (old location, OL) were compared. Two‐way ANOVA interaction F _(3,51) = 21.06, p < 0.0001, OL vs. NL, Holm–Sidak's test, p < 0.0001 for wild‐type, nonsignificant for 5xFAD, p < 0.0001 for PKRKO, and p < 0.0001 for DM. (b) Performances in the starmaze. S1, S2 = session number (5 trials per session). Repeated measures ANOVA, genotype effect p = 0.0184, sessions effect p < 0.0001, interaction F _(7,100) = 18.96, post hoc Holm–Sidak's test. (c) Anxiety assessment in the elevated plus maze. Time in open arm between 5xFAD and double‐mutant mice: Kruskal–Wallis test p < 0.0001, post hoc Mann–Whitney test. (d) PET scan analysis of amyloid burden in PKRKO, 5xFAD, and DM mice (n = 4–6 per group). All results are expressed as the standard uptake value ratio (SUVr) relative to the cerebellum. (e, f) Quantification of Aβ levels in the hippocampus of 30‐week‐old mice by immunoblot analysis (e) with GAPDH used as the loading control, and by ELISA analysis (f) (n = 6 mice per group). Kruskal–Wallis, p < 0.0001, Dunn's post hoc test. (g) BACE1 levels in the hippocampus of 30‐week‐old mice (n = 10 mice per group). Kruskal–Wallis, p = 0.0011, Dunn's post hoc test. (I) Aβ immunohistochemistry with Moab antibody, revealed with horseradish peroxidase, in the subiculum of 30‐week‐old mice (n = 5 mice per group). Significant reduction of Aβ load in double‐mutant mice after quantification. Mann–Whitney test, p = 0.016. (a–h) Data are means ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001