Objective To investigate the regulatory effect and molecular mechanism of annexin A5 (AnxA5)gene on cognitive function in mice. Methods AnxA5 gene knockout (AnxA5^{- / -}) mice were constructed by CRISPR/Cas9 technology. The regulatory effect of AnxA5 on cognitive function in mice was verified by Morris water maze, Ymaze and novel object recognition tests. Western blot, qPCR, immunofluorescence, real-time cell analysis (RTCA) and other method were used to detect the effects of AnxA5 deletion on the proliferation and morphology of mouse hippocampal neurons, and to explore its regulatory mechanism. APP / PS1 double transgenic mice were used as positive controls for Alzheimer’ s disease. Results Compared with wild-type (WT) C57BL / 6 mice, the cognitive function of AnxA5^{- / -}mice was significantly reduced(P<0. 05). After interfering with the expression of AnxA5 gene in HT-22 cells, the cell proliferation ability was significantly weakened(P<0. 05), the cell morphology was irregular,and AnxA5 deletion could activate the P65 signaling pathway. Conclusions AnxA5 gene deletion can up-regulate the expression level of inflammatory factors by activating the P65 pathway, thereby damaging mouse hippocampal neurons and ultimately leading to cognitive impairment in mice.