Fig. 5
From: Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy
Pyk2 expression is protective against Tau-mediated early death and spatial memory impairment in PS190/+ animals. A, Kaplan-Meier survival curve of WT, Pyk2−/−, PS190/+ and PS190/+;Pyk2−/− animals. Survivorship of PS190/+;Pyk2−/− mice (median survival, 270 days) is significantly reduced compared to PS190/+ animals (median survival, 429.5 days). Log-rank (Mantel-Cox) test, **p = 0.0085, n = 6–7 mice. B–D, Spatial memory of 9–10-month-old mice was assessed using the MWM test. B, Latency is defined as the time required to reach a hidden platform across 6 acquisition sessions of 4 trials each. Across the final 4 acquisition sessions, PS190/+;Pyk2−/− animals took significantly longer to reach the platform compared to WT mice. Data are graphed as mean ± SEM, repeated measures ANOVA with Tukey HSD multiple comparisons test, **p = 0.002, n.s. = not significant (p = 0.343), n = 9–17 mice. C, A 60 s probe trial was performed 24 h after the final acquisition session with the hidden platform removed. WT, Pyk2−/− and PS190/+ mice spent significantly greater time in the target quadrant compared to the opposite quadrant, while the difference in time spent between the target and opposite quadrants failed to reach significance for PS190/+;Pyk2−/− animals. Data are graphed as mean ± SEM, unpaired two-tailed t-test, *p < 0.05, ***p < 0.001, ****p < 0.0001, n.s. = not significant (p = 0.2885), n = 9–17 mice. Dashed line, 25%. D, To rule out visual impairment, latency for animals to find a platform marked with a visual cue was assessed following the probe trial. 4 animals (2 Pyk2−/−, 1 PS190/+ and 1 PS190/+;Pyk2−/−) were unable to locate the visible platform after 15 trials and were excluded from all MWM analyses. When excluding these animals, there were no significant differences in the time required to reach the visible platform across genotypes. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, n = 9–17 mice. E, Animal body weights of 9–10-month-old mice across genotypes. PS190/+ weighed significantly less than WT animals while PS190/+;Pyk2−/− animals weighed significantly less than both WT and Pyk2−/− mice. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, **p < 0.01, ****p < 0.0001, n = 18–23 mice. F, A rotarod test was performed to assess motor coordination. Latency to fall off the accelerating drum (acceleration: 0.1 rotations/min/sec; top speed: 4 rotations/min) over 5 consecutive trials was assessed and the best time (longest latency) for each animal compared. There were no significant differences in longest latency to fall across genotypes. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, n = 11–17 mice. G, A wire hang test was conducted to assess grip strength. Animals were placed in the center of a wire grid (1 cm by 1 cm) and the latency to fall from the inverted grid was determined across 2 120 s trials. Mean latencies to fall across the 2 trials are plotted in G. There were no significant differences in mean latency to fall across genotypes. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, n = 11–17 mice. H–J, Gait assessment was conducted using a Noldus CatWalk XT system. H, There were no significant differences in mean run speed across genotypes. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, n = 5–11 mice. I, There were no significant differences in step sequence regularity index across genotypes. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, n = 5–11 mice. J, There were no significant differences in mean maximum run variation across genotypes. Data are graphed as mean ± SEM, one-way ANOVA with Tukey’s multiple comparisons test, n = 5–11 mice