Ketamine Promotes Alzheimer’s-Like Neurodegeneration by Activating Glycogen Synthase Kinase 3 Beta and Inhibiting Protein Phosphatase 2A

Abstract

To investigate the mechanism of ketamine promoting Alzheimer’s-like neurodegeneration in mice. 24 male 8 w old Kunming mice of specific pathogen-free grade were randomly divided into a blank control group (control group) and a ketamine intervention group (experimental group) according to the random number table, 12 mice in each group. The mice in the experimental group were given ketamine injection at the dose of 30 mg/kg. Mice in the control group were given an equal volume of normal saline injection. The intervention was conducted once a day for consecutive 6 mo. The behavioral changes of the mice in the two groups were compared. Western blot was used to detect the expression levels of tau (phospho Thr231), tau (phospho S396), tau (phospho Ser404), glycogen synthase kinase 3 beta, glycogen synthase kinase 3 beta (phospho ser9) and protein phosphatase 2A proteins in the brain tissue of hippocampus and the ratio of phosphorylated tau protein to tau protein was calculated. The expressions of beta-amyloid protein and tau protein in the hippocampus were observed by immunohistochemistry. The results of the Morris water maze showed that the escape latency of mice in both groups was gradually decreased and the escape latency of mice in the control group was lower than that in the experimental group. Besides, the times of crossing target platform and the proportion of activity time in target quadrant of mice in the experimental group were lower than those in the control group. At the same time, compared with the control group, the expression levels of tau (phospho Thr231) and tau (phospho Ser404) were decreased in the experimental group, and the expressions of tau (phospho S396), glycogen synthase kinase 3 beta, glycogen synthase kinase 3 beta (phospho ser9) and protein phosphatase 2A proteins were increased. Compared with the control group, the expression of beta-amyloid protein in the experimental group was significantly reduced and the opalescence density of beta-amyloid protein was significantly lower than that in the control group (p<0.05). Long-term use of ketamine can lead to up-regulated expression of beta-amyloid protein and tau protein in mice hippocampus, which may induce hyperphosphorylation of tau protein at Thr231, S396 and S404 by activating glycogen synthase kinase 3 beta and inhibiting protein phosphatase 2A, causing cognitive function decline in mice.