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Fig. 2 | Acta Neuropathologica Communications

Fig. 2

From: Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway

Fig. 2

Lack of p-GR sites causes neurodystrophies, learning and memory deficits in the APP/PS1 model without impacting amyloid deposition and cerebrovascular pathology. a Experimental timeline in triple transgenic mice. b Survival over 9 months: effects of APP/PS1 (Chi2 = 26.9 df = 3, P < 0.001) and Nr3c1ki/ki (Chi2 = 1.3 df = 1, P = 0.25). c Primary latency to find the hidden platform in the Barnes maze during training (days 1–4) and recalls (days 6 and 14). Means ± SEM of N(3,6,9 months) = 10,9,9 Nr3c1+/+, 9,9,9 Nr3c1ki/ki, 12,8,8 Nr3c1+/+-APP/PS1, 14,10,10 Nr3c1ki/ki-APP/PS1 mice. Two-way ANOVA: effect of genotype F7,68 = 4.7, P = 0.0002; effect of time F5,332 = 63.3, P < 0.0001 post-hoc Tukey test *P < 0.05. d Percentage of alternance between arms of a Y-maze. Means ± SEM of N(3,9 months) = 12,9 Nr3c1+/+, 12,9 Nr3c1ki/ki and N(3,6,9 months) = 7,7,6 Nr3c1+/+-APP/PS1, 13,13,5 Nr3c1ki/ki-APP/PS1 mice. Two-way ANOVA analyses show no effect of genotype or aging P > 0.05. e Time exploring the new object over the old one presented 24 h earlier in the novel object recognition test. Means ± SEM expressed as ratio index in N(3,6,9 months) = 15,15,13 Nr3c1+/+, 16,16,11 Nr3c1ki/ki, 10,8,5 Nr3c1+/+-APP/PS1, 16,9,5 Nr3c1ki/ki-APP/PS1 mice. Three-way ANOVA: effect of APP/PS1 F1,127 = 18.3; effect of Nr3c1ki/ki F1,127 = 20.6; effect of aging F2,127 = 16.9, P < 0.0001 post-hoc Tukey test *p < 0.05. f Time exploring the new mouse over the old one presented 24 h earlier in the 3-chamber test. Means ± SEM expressed as ratio index in N(3,6,9 months) = 12,10,9 Nr3c1+/+, 12,10,9 Nr3c1ki/ki, 10,8,6 Nr3c1+/+-APP/PS1, 16,11,5 Nr3c1ki/ki-APP/PS1 mice. Three-way ANOVA: effect of APP/PS1 F1,106 = 7; effect of Nr3c1ki/ki F1,1106 = 11.9; effect of aging F2,106 = 6, P < 0.005 post-hoc Tukey test *p < 0.05. g Repeat images of a cortical volume in somatosensory cortex of Nr3c1+/+ mouse at 3, 6 and 9 MO to track in 3D the amyloid plaques (methoxy-XO4), blood vessels (75KDa dextran-AlexA594) and pyramidal neurons of layer 5 (thy1-YFP). h Surface of parenchyma and vascular amyloid plaques. Means ± SEM of N(3,6,9 months) = 11,7,5 Nr3c1+/+-APP/PS1, 13,11,7 Nr3c1ki/ki-APP/PS1 mice. Not determined (n.d). Two-way ANOVA: effect of genotype F1,22 = 1.9, P = 0.18; effect of aging F2,26 = 34.3, P < 0.0001. i Oligomeric amyloid detected with A11 antibody in somatosensory cortex (5 μg and 1/5 serial dilutions) of Nr3c1+/+-APP/PS1 and Nr3c1ki/ki-APP/PS1 mice (8 months old) against a range of diluted Aβ42 oligomers prepared in vitro. j Flow and adhesion of blood cells in amyloid-covered vessels. Means ± SEM of N(3,6,9 months) = 6,6,6 Nr3c1+/+-APP/PS1, 8,8,6 Nr3c1ki/ki-APP/PS1 mice. Two-way ANOVA: effect of time on adhesion F1,20 = 5.2, P = 0.015; no effect on flow. k Number of dystrophic axons and dendrites of pyramidal neurons in somatosensory cortex. Means ± SEM of N(3,6,9 months) = 3,3,3 Nr3c1+/+, 3,3,3 Nr3c1ki/ki, 9,5,3 Nr3c1+/+-APP/PS1, 12,8,4 Nr3c1ki/ki-APP/PS1 mice. Three-way ANOVA: effect of APP/PS1 on axons F1,23 = 52.9, P < 0.0001 and dendrites F1,19 = 2.7; effect of Nr3c1.ki/ki on axons F1,23 = 6.1 and dendrites F1,14 = 9.1, P < 0.01; effect of aging on axons F2,24 = 26 and dendrites F2,28 = 26.2, P < 0.0001 post-hoc Tukey test *P < 0.05

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