Objective:To detect, compare and analyze the activity and significance of CREB1 protein in the hippocampus of Alzheimer’s disease (AD) and wild type control mice. Methods:Continuous intraperitoneal injection of D-galactose 90 mg/(kg·d) and AlCl3 40 mg/(kg·d) for 90 days was performed to mice to make AD mouse model. Preliminary appraise of AD model was performed by sucrose preference test and Y-maze test. CREB1, p-CREB1 protein expression levels in the hippocampal CA1, CA3 and DG areas of AD and wild type control mice were compared by immunohistochemical detection, respectively. Results:Compared with the control group, the sucrose preference percentage of AD mice decreased significantly (P < 0.01). The spatial discrimination ability of the AD group was significantly lower than that of the wild-type control group (P < 0.01). Compared with the wild type control group, the positive expressions of CREB1 and p-CREB1 proteins in the hippocampal CA1, CA3 and DG areas were significantly decreased in AD mice (P < 0.01). Conclusion:By inhibiting the activity of key nuclear transcription factor CREB1 in hippocampal tissues, D-galactose combined with AlCl3 affect neuronal survival, post injury repair and regeneration of nerve cells, resulting in ability of learning and memory impaired, thereby causing the occurrence and development of AD.