Background and Purpose：Alzheimer’s disease (AD) is a neurodegenerative disease whose main clinical symptoms are cognitive impairment. Synaptic dysfunction is currently a widely accepted pathogenic factor for AD, and this process is closely related to abnormalities in the glutamate receptor /cyclic adenosine monophosphate response element binding protein (NMDAR/CREB) signaling pathway is closely related. The purpose of this study was to identify a new drug for AD treatment. Experimental Approach: PC12 cells, primary neuron model and APPswe/PSEN1dE9(APP/PS1) transgenic mouse model were studied using Aβ1-42 oligomer intervention. Combined with the treatment of AS-IV and NMDAR inhibitors, RT-qPCR, Western-blotting, immunofluorescence and behavioral analysis were performed to explore the pharmacological action and possible mechanism of AS-IV. Key Results: AS-IV significantly improved synaptic damage in AD models and up-regulated the expression of NMDAR (NR1, NR2A, NR2B), CaMKs (CaMKII, CaMKIV), CREB and BDNF. Ultimately, learning, memory, and cognitive impairments in APP/PS1 mice were improved. Inhibition of NMDAR expression significantly attenuated the related protective function of AS-IV. Conclusion and Implications: AS-IV effectively exerts its anti-AD function by activating the NMDAR /CREB signaling pathway. This could help in the development of drugs to treat AD.