Objective:To investigate the effect and mechanism of Toll-like receptor 2 (TLR2) on cognitive function in obese mice.Methods:Male C57BL/6J and TLR2 knockout mice were divided into control group, obesity group, TLR2 knockout group, and TLR2 knockout obesity group according to standard diet or high-fat diet. After 16 weeks, water maze experiments were performed to test the learning and memory ability of mice in each group. The body weight and blood lipid biochemical indexes of the mice in each group were measured. Immunohistochemical analys was used to detect amyloid-β (Aβ) protein expression in the hippocampus. Western blotting was used to detect the expression of nuclear factor-κB (NF-κB) p65, phosphorylated (p-) NF-κB p65, low density lipoprotein receptor-related protein 1 (LRP1), and Aβ protein.Results:Compared with the standard control group, the expressions of TLR2, NF-κB p65, p-NF-κB p65, and Aβ protein in obesity group were significantly increased, LRP1 protein expression level was reduced, and the learning and memory ability of mice was significantly reduced. Compared with the obese group, the expression levels of NF-κB p65, p-NF-κB p65, and Aβ protein in the TLR2 gene knockout obesity group decreased, while the expression level of LRP1 protein increased. The memory and learning ability of these mice was significantly improved.Conclusion:TLR2 deficiency may improve the cognitive function of obese mice by inhibiting the TLR2/NF-κB pathway. The mechanism may be related to the up-regulation of LRP1 protein expression.