Abstract: Objective: To investigate the effect of sericin on cognitive impairment in rats with diabetes mellitus (DM) complicated with atherosclerosis(AS). Methods: A DM + AS rat model was established using streptozotoxocin(STZ)+vitamin D₃. Forty-eight DM+AS rats were randomly divided into model group, 400 mg/kg and 800 mg/kg sericin group, and inhibitor group (800 mg/kg sericin+LY294002 group), with 12 rats in each group, and another 12 male rats were selected as the control group. The rats of the sericin group and 800 mg/kg sericin+LY294002 group were given the corresponding dose of sericin solution for 42 days, and the rats of the control and model group were given equal volume of distilled water. The rats of the 800 mg/kg sericin+LY294002 group were injected with PI3K/AKT inhibitor LY294002 solution in the lateral ventricles 1 week before the end of the experiment. At the end of the experiment,the Morris water maze was used to detect the learning and memory ability of rats, and the glucose tolerance of the rats was detected. The AS indexes C-reactive protein(CRP), matrix metalloproteinase-9(MMP-9) and hippocampal inflammatory factorsinterleukin(IL)-Iβ, IL-18, tumor necrosis factor-α(TNF-α) were detected by enzyme-linked immunosorbent assay(ELISA). Thoracic aorta and hippocampal tissue morphology were observed by hematoxylin and eosin(HE) staining, and the fluorescence intensity of microglial marker Iba-1 was detected by immunofluorescence. The protein expression of PI3K/AKT pathway was detected by western blotting. Results: Compared with the control group, the blood glucose value, serum levels of CRP and MMP-9 of the rats in the model group were increased significantly(all P＜0.05), and thoracic aorta was damaged. The swimming trajectories were more complex, the escape latency was prolonged, and the frequency of crossing platform was decreased in the model group(all P＜0.05). The hippocampus was damaged, and the contents of hippocampal IL-18, IL-1β, TNF-α, and the fluorescence intensity of Iba-1 were increased in the model group(all P＜0.05). The expression of hippocampal PI3K, pPI3K and p-AKT were also decreased in the model group(all P＜0.05). Compared with the model group, the blood glucose and the serum contents of CRP and MMP-9 were decreased(all P＜0.05), and the damage to thoracic aorta was alleviated to some extent in the sericin group. The hippocampal damage was improved, the contents of inflammatory factors and the fluorescence intensity of Iba-1 were decreased in the sericin group(all P＜0.05). The expression of hippocampal PI3K, p-PI3K and p-AKT were increased, and the memory and learning ability were improved(all P＜0.05). After inhibiting PI3K/AKT, the improvement and anti-inflammatory effect of sericin on hippocampal injury, and the improvement effect of learning and memory ability in rats were weakened(all P＜0.05). Conclusion: Sericin may improve cognitive impairment in DM+AS rats by inhibiting neuroinflammation through the PI3K/AKT pathway.