Abstract: This study is to investigate the protective effect of rosiglitazone (RSG) against learning andmemory impairment of APP/PS1/tau transgenic mice.AD mice model was replicated by using 6-month APP/PS1/tau transgenic mice.The learning and memory ability of mice was evaluated by Morris water maze and Western blotting assays was applied to measure the phosphorylation and O-glycosylation of Tau andneurofilaments (NFs) protein.The results demonstrated that RSG could reverse the learning and memory deficits of 3×Tg mice significantly.It was also found that RSG could suppress the hyperphosphorylation of Tau and NFs protein levels and increase the glycosylation expression of Tau and NFs proteins in 3×Tg mice brain.Together, RSG ameliorates cognitive impairments of 3×Tg mice via the alleviation of the hyperphosphorylated Tau and NFs proteins burden in the brain.