Molecular mechanism of adiponectin in alleviating the anxiety- and depression-like behaviors in triple transgenic Alzheimer's disease model mice

Abstract

Objective To observe the effects of adiponectin (APN) on anxiety- and depression-like behaviors occurred in APP/PS1/tau triple transgenic Alzheimer’s disease (3xTg-AD) model mice and investigate the possible mechanism. Methods The 9-month-old 3xTg-AD mice and wild type (WT) mice were randomly divided into four groups (n=8 for each group): WT+ Saline, WT+ APN, 3xTg-AD+ Saline and 3xTg-AD+ APN groups. The mouse was chronically intracerebroventricular injection of APN or saline under free moving condition.Elevated plus maze task was used to evaluate the anxiety-like behaviors.Sucrose preference test and tail suspension test were used to evaluate the depression-like behaviors. Western blot was used to detect the protein expression levels of p-AMPK, AMPK, p-GSK-3β (Ser9), GSK-3β and SIRT1 in the hippocampus of each mouse. Results In the elevated plus maze test, the time percentage spent in open arms of 3xTg-AD+ Saline mice was ((4.2±2.7)%), which significantly lower than that in WT+ Saline group ((10.1±4.1)%)(q=4.349, P<0.01) and in 3xTg-AD+ APN group ((9.7±3.3)%)(q=4.065, P<0.01). In the sucrose preference test, the sucrose preference percentage in 3xTg-AD+ Saline group((48.8±5.3)%) was lower than that in WT+ Saline group ((60.9±6.7)%)(q=4.522, P<0.01) and in 3xTg-AD+ APN group ((59.3±6.2)%)(q=3.911, P<0.05). As for tail suspension test, the immobility time percentage in 3xTg-AD+ Saline group((40.7±9.9)%) was higher than that in WT+ Saline group ((27.1±4.8)%)(q=5.257, P<0.001) and in 3xTg-AD+ APN group ((31.4±6.0)%)(q=3.624, P<0.05). The result of Western blot showed that there was no significant difference in expression level of AMPK and GSK-3β among four groups. However, compared with that in WT+ Saline group, the expression levels of p-AMPK (q=3.586, P<0.05), p-GSK-3β (Ser9) (q=3.125, P<0.05), and SIRT1 (q=3.044, P<0.05) in 3xTg-AD+ Saline group were significantly decreased. In addition, compared with that in 3xTg-AD+ Saline group, the expression levels of p-AMPK (q=3.374, P<0.05) and p-GSK-3β (Ser9) (q=3.063, P<0.05) in 3xTg-AD+ APN group were obviously up-regulated without affecting the SIRT1. Conclusion Adiponectin can effectively alleviate the anxiety- and depression-like behaviors of 9-month-old 3xTg-AD mice by up-regulating the protein expression of p-AMPK and p-GSK-3β (Ser9) in the hippocampus. Key words: Adiponectin; Alzheimer’s disease (AD); APP/PS1/Tau triple-transgenic AD (3xTg-AD) mice; Anxiety; Depression