RNA Interference Silencing of Glycogen Synthase Kinase 3ß Inhibites Tau Phosphorylation in Mice with Alzheimer Disease.

ABSTRACT

To explore the effect of glycogen synthase kinase 3ß (GSK-3ß) silencing on Tau-5 phosphorylation in mice suffering Alzheimer disease (AD). GSK-3ß was firstly silenced in human neuroblastoma SH-SY5Y cells using special lentivirus (LV) and the content of Tau (A-12), p-Tau (Ser396) and p-Tau (PHF-6) proteins. GSK-3ß was also silenced in APP/PS1 mouse model of AD mice, which were divided into three groups (n = 10) AD, vehicle, and LV group. Ten C57 mice were used as control. The memory ability of mice was tested by square water maze, and the morphological changes of hippocampus and neuron death were analyzed by haematoxylin-eosin staining. Moreover, the levels of Tau and phosphorylated Tau (p-Tau) were detected by western blotting and immunohistochemistry, respectively. The lentivirus-mediated GSK-3ß silencing system was successfully developed and silencing GSK-3ß at the cellular level reduced Tau phosphorylation obviously. Moreover, GSK-3ß silence significantly improved the memory ability of AD mice in LV group compared with AD group (P < 0.05) according to the latency periods and error numbers. As for the hippocampus morphology and neuron death, no significant change was observed between LV group and normal control. Immunohistochemical detection and western blotting revealed that the levels of Tau and p-Tau were significantly down-regulated after GSK-3ß silence. Silencing GSK-3ß may have a positive effect on inhibiting the pathologic progression of AD through down-regulating the level of p-Tau.