Crocin alleviates cognitive impairment associated with atherosclerosis via improving neuroinflammation in LDLR−/− mice fed a high‐fat/cholesterol diet

Abstract Crocin has been extensively investigated in treating neurodegenerative diseases. However, its effect on cognitive impairment associated with atherosclerosis remains unknown. The present study aimed to explore the potential mechanism of crocin on cognitive impairment in a mouse model of atherosclerosis. LDLR −/− mice fed a high‐fat/cholesterol diet were administered variable‐dose crocin for 56 days through gavage. Biochemical tests showed that serum triglycerides and circulating lipopolysaccharide decreased in mice treated with crocin. Behavioral tests indicated that crocin alleviated cognitive impairment by reducing latency to the platform and increasing the swimming distance in the target quadrant. This mechanism might be associated with crocin inhibiting Aβ deposition by decreasing Aβ1‐42 and tau phosphorylation. Crocin improved neuroinflammation by inhibiting the increase in reactive microglia and astrocytes, weakening NLRP3 inflammasome activation accompanied by a reduction in Caspase‐1 and IL‐1β, and blocking TLR4 signaling accompanied by a decrease in NF‐kB p65 and MyD88. In addition, crocin raised the protein expression of ZO‐1 and occludin. These findings provide experimental support that crocin attenuates cognitive impairment associated with atherosclerosis by repressing neuroinflammation, which is attributed to its suppression on the activation of microglia and astrocytes, and the production of inflammatory cytokines via targeting the NLRP3 inflammasome and TLR4 signaling.