OBJECTIVE: To observe the effect of tetrahydroxy stilbene glucoside (TSG) on the behavior of APP695V717I transgenic mouse models and the expression of autophagy-associated proteins Beclin-1 and LC3- II. METHODS: Forty 3-month-old APP695V717I transgenic mice were randomized equally into either a TSG group (n = 20) or a model group (n = 20). A normal control group consisted of C57BL/6J mice of the same age and background (n = 20). The TSG group received TSG intragastric administration for 1 month. Behavior was measured using the Morris water maze and the Y-maze tests. Changes in protein expression and mRNA of autophagy-associated Beclin-1 and LC3- II in mice hippocampus were detected by western blot and Reverse Transcription-Polymerase Chain Reaction (RT-PCR) analyses. RESULTS: The number of electric-stimulus escapes significantly increased and the Morris water maze test showed prolonged escape latency, greater swimming distance, less time taken to cross the exact former platform location in the model group, and increased mRNA and protein expressions of Beclin-1 and LC3- II compared with the control group (P < 0.05). The TSG group showed a decrease in the number of electric-stimulus escapes, shorter escape latency and swimming distance, greater time taken to cross the exact former platform location, and decreased mRNA and protein expressions of Beclin-1 and LC3-ll compared with the model group (P < 0.05). CONCLUSION: These results indicate that tetrahydroxy stilbene glucoside can decrease expressions of Beclin-1 and LC3- II in the autophagy pathway. It can attenuate injury to endoplasmic reticulum functions caused by Ab neurotoxicity, improving learning, memorizing, and spatial orientation behavior in mice. (C) 2015 JTCM. All rights reserved.