Fig. 4: Trametinib induces neuroregeneration and recovers functional impairment.

a Scheme of trametinib administration to 5XFAD mice for (b) and (c). Trametinib was administered to 5-month-old 5XFAD mice for 2.5 months. b, c Analysis of the cortex from 7.5-month-old 5XFAD mice. Sagittal sections of the cortex were immunostained for NeuN and Tau. The number of NeuN+ cells was counted in cortical layer V. n = 14 serial sagittal sections from each mouse, n = 3 mice per group. Normalized by cortical layer V area and renormalized to the WT-vehicle group. The length of tau-stained cells was measured in cortical layer V. n = 3 mice per group. P values were obtained by one-way ANOVA. d Scheme of trametinib administration experiments with 5XFAD mice for (e) and (f). Trametinib was administered to 12-month-old 5XFAD mice for 1 month. e, f Analysis of the cortex from 13-month-old 5XFAD mice. Sagittal sections of the cortex were immunostained for NeuN and Tau. The number of NeuN+ cells was counted in cortical layer V and subiculum. n = 21 serial sagittal sections from each mouse, n = 3 mice per group. Normalized by cortical layer V area and renormalized to the 5XFAD-vehicle group. Scale bars, 50 μm. The length of tau-stained cells was measured in cortical layer V. n = 3 mice per group. g Nine-month-old 5XFAD mice were administered vehicle or trametinib for 1.5 months. A fear conditioning test was performed, and the average freezing % in 2 min was calculated. n = 12 mice for the WT-vehicle group, n = 22 mice for the 5XFAD-vehicle group, n = 11 for the 5XFAD-trametinib group. P values were obtained by one-way ANOVA. h Seven-month-old 5XFAD mice were administered vehicle or trametinib for 1.5 months. A novel object recognition test was performed. Heatmap analysis of animal tracking following the novel object recognition test (left panel) and the discrimination index in 5 minutes was calculated (right panel). n = 5 mice for the WT-vehicle group, n = 5 mice for the 5XFAD-vehicle group, n = 8 for the 5XFAD-trametinib group. Data are representative of three independent experiments, and values are expressed as the mean ± SEM. P values were obtained by one-way ANOVA (c, g) and Student’s t test (f, h). *p < 0.05 and ***p < 0.001. Data quantification was performed blindly with respect to the experimental group.