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Fig. 7 | Alzheimer's Research & Therapy

Fig. 7

From: Serotonin 5-HT6 receptors affect cognition in a mouse model of Alzheimer’s disease by regulating cilia function

Fig. 7

SB271046 restored cognitive impairment of APP/PS1 mice in the Morris water maze test. (a) Morphology of the AIS in APP/PS1 and WT mice. AC3 (red) indicated primary cilia. NF186 (purple) indicated the AIS. (b) AIS length was significantly increased in APP/PS1 neurons. Distance between the AIS and cell body was reduced in APP/PS1 neurons. Percentage of branched AIS increased in APP/PS1 neurons. AIS length, **p < 0.01 (Mann–Whitney U test); distance to cell body, *p < 0.05 (Mann–Whitney U test); branched AIS, **p < 0.01 (Mann–Whitney U test). (c) 5-HT6 siRNA reversed AIS morphological changes in APP/PS1 neurons. AIS length, **p < 0.01 (Mann–Whitney U test); distance to cell body, **p < 0.01 (Mann–Whitney U test); branched AIS, **p < 0.01 (Mann–Whitney U test). (d) 5-HT6 antagonist SB271046 had no effect on swimming speed. SB271046 decreased swimming distance and time to reach the platform, and increased time spent in the target quadrant and number of crossings. Compared with WT mice, APP/PS1 mice had obvious cognitive impairment, containing longer swimming distance and time to platform and short time in target quadrant and number of crossings. Swimming speed (two-way ANOVA: interaction, F 1,104 = 0.09, p = 0.77; treatment, F 1,104 = 0.06, p = 0.81; gene, F 1,104 = 1.38, p = 0.24). Swimming distance: vehicle versus SB271046 in WT, *p < 0.05; vehicle versus SB271046 in APP/PS1, *p < 0.05; WT versus APP/PS1 in vehicle, **p < 0.01 (two-way ANOVA: interaction, F 1,104 = 0.11, p = 0.74; treatment, F 1,104 = 11.15, p < 0.01; gene, F 1,104 = 16.99, p < 0.001). Time to platform (three-way ANOVA: day, F 5,536 = 118.8, p < 0.001; treatment, F 1,536 = 17.62, p < 0.001; gene, F 1,536 = 29.06, p < 0.001; day × treatment, F 5,536 = 1.08, p = 0.37; day × gene, F 5,536 = 1.04, p = 0.39; treatment × gene, F 1,536 = 0.2, p = 0.65; day × treatment × gene, F 5,536 = 0.33, p = 0.9). Time in target quadrant: vehicle versus SB271046 in WT, *p < 0.05; vehicle versus SB271046 in APP/PS1, *p < 0.05; WT versus APP/PS1 in vehicle, *p < 0.05 (two-way ANOVA: interaction, F 1,101 = 0.02, p = 0.88; treatment, F 1,101 = 9.64, p < 0.01; gene, F 1,101 = 9.88, p < 0.01). Crossing times: vehicle versus SB271046 in WT, *p < 0.05; vehicle versus SB271046 in APP/PS1, **p < 0.01; WT versus APP/PS1 in vehicle, *p < 0.05 (two-way ANOVA: interaction, F 1,104 = 0.02, p = 0.88; treatment, F 1,104 = 9.76, p < 0.01; gene, F 1,104 = 10.47, p < 0.01). (e) SB271046 decreased cilia length after water maze of 7 days in vivo. (f) SB271046 restored the longer cilia of APP/PS1 mice. Vehicle versus SB271046 in WT, *p < 0.05; vehicle versus SB271046 in APP/PS1, *p < 0.05; WT versus APP/PS1 in vehicle, **p < 0.01 (two-way ANOVA: interaction, F 1,268 = 0.05, p = 0.82; treatment, F 1,268 = 9.25, p < 0.01; gene, F 1,268 = 15.49, p < 0.001). (g) SB271046 recovered AIS morphology in vivo. AnkG indicated AIS of neuron. Arrows indicate AIS. Calbindin indicated neuron. (h) SB271046 decreased AIS length, increased distance from AIS to cell body, and deceased percentage of branched AIS of neuron. AIS length: vehicle versus SB271046 in WT, *p < 0.05; vehicle versus SB271046 in APP/PS1, ***p < 0.001; WT versus APP/PS1 in vehicle, **p < 0.01 (two-way ANOVA: interaction, F 1,223 = 5.37, p < 0.05; treatment, F 1,223 = 23.45, p < 0.001; gene, F 1,223 = 4.91, p < 0.05). Distance to cell body: vehicle versus SB271046 in WT, *p < 0.05; vehicle versus SB271046 in APP/PS1, *p < 0.05; WT versus APP/PS1 in vehicle, *p < 0.05 (two-way ANOVA: interaction, F 1,222 = 0.86, p = 0.36; treatment, F 1,222 = 12.15, p < 0.001; gene, F 1,222 = 4.96, p < 0.05). Branched AIS: vehicle versus SB271046 in WT, p = 0.79; vehicle versus SB271046 in APP/PS1, ***p < 0.001; WT versus APP/PS1 in vehicle, ***p < 0.001 (two-way ANOVA: interaction, F 1,8 = 87.61, p < 0.001; treatment, F 1,8 = 95.26, p < 0.001; gene, F 1,8 = 94.72, p < 0.001). Scale bars, 10 μm. All data presented as mean ± SEM (≥3 independent experiments). 5-HT6, serotonin 6 receptor, AIS axon initial segment, DAPI 4',6-diamidino-2-phenylindole, EGFP enhanced green fluorescent protein

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