Objective To investigate the possible mechanism of action of Heixiaoyao Powder（ 黑逍遥散） in the treatment of Alzheimer’ s disease. Methods A total of 30 APP/PS1 double transgenic male mice were randomly divided into a model group

a donepezil hydrochloride group and a Heixiaoyao Powder group

with 10 rats in each group. Ten wild-type C57 BL/6 male mice of the same age and same strain were set as blank group. The Heixiaoyao Powder group was given 6 g/（ kg·d） by intragastric administration

and donepezil hydrochloride was given 3. 25 mg/（ kg·d） to the donepezil hydrochloride group. The model group and the blank group were given double distilled water 0. 2 ml/10 g by gavage. All groups were intragastrically administered once a day for 3 months. The Morris water maze was used to observe the escape latency during the 1 st to 5 th day of the experiment

and the space search experiment was recorded on the 6 th day to record the number of times across the original platform. The expression of cyclic adenosine responsive element binding protein 1（ CREB1） and phosphorylated cyclic adenosine responsive element binding protein 1（ p-CREB1） in mouse hippocampal CA1

CA3 and DG regions were detected by immunohistochemistry. Results Compared with the blank group

the escape latency of the model group was significantly prolonged on the 1 st to 5 th day

and the number of trans-platforms was significantly decreased on the 6 th day. The expression of CREB1 and p-CREB1 protein in the hippocampus CA1

CA3 and DG areas was significantly decreased（ P < 0. 05 or P < 0. 01）. Compared with the model group

the escape latency of the donepezil hydrochloride group and the Heixiaoyao Powder group was shortened at each time point

and the number of trans-platforms increased significantly on the 6 th day. The expression of CREB1 and p-CREB1 protein in the hippocampus CA1

CA3 and DG areas of the mice increased significantly（ P < 0. 05 or P < 0. 01）. There was no significant difference between the indicators of Heixiaoyao Powder and Donepezil Hydrochloride（ P > 0. 05）. Conclusion Heixiaoyao Powder may play a role in the prevention and treatment of Alzheimer’s disease by regulating hippocampal CREB1 and its phosphorylation expression.