Abstract： Objective To investigate the effect of TLR2 in mediating the pathological activa-tion of microglia and neuronal injury in vascular dementia(VaD)rat model and its molecular mechanisms.Methods In vitro experiments were carried out by using LPS-induced activation of hu-man microglia cell line HMC3 cells.The proliferation ability of HMC3 cells was determined by CCK-8 assay.Systemic TLR2 knockdown was performed by using Adv-TLR2 shRNA or Adv-shRNA NT.The VaD rat model was established by permanent bilateral common carotid artery occlusion(2VO).The expression levels of TLR2,NF-κB,Iba-1,Claudin-5 and ZO-1 in HMC3 cells and rats'white matter tissues were determined by Western blotting.The levels of inflammatory cytokines IL-6,IL-1β and TNF-α,and the ferroptosis-related indicators of Fe2+,malondialdehyde(MDA)and glutathione(GSH)in rats'white matter tissues were determined by ELISA.Morris water maze(MWM)test was used to determine rats'brain neuronal injury.Results The expression levels of TLR2,NF-κB and Iba-1 in the LPS group were enhanced when compared with those in the Control group(P<0.05).The expression levels of the above proteins in the Adv-TLR2 shRNA group were decreases when compared with those in the LPS groups(P<0.05).The expression levels of TLR2/NF-κB and Iba-1 were up-regulated,and those of Claudin-5 and ZO-1 were down-regulated in the white matter tissues of Model group rats,when compared with those of the Sham group,(P<0.05).In addition,the levels of inflammatory cytokines IL-6,IL-1β and TNF-α were up-regulated(P<0.05),the Fe2+and MDA levels were increased,and the GSH levels were decreased(P<0.05).TLR2 knockdown had reversed the values of above indicators in the Model+Adv-TLR2 shR-NA group when compared with those in the Model group(P<0.05).Morris water maze test showed that rats in the Model group and Model+Adv-TLR2 shRNA group took longer time to find the target quadrant(upper left quadrant)(P<0.05),stayed shorter time in the target quadrant(P<0.05)when compared with those in the Sham group,the swimming routes of rats in the four quad-rants of MWM were evenly distributed.Compared with Model group,the Model+Adv-TLR2 shRNA group showed a reversion in the values of above indicators and had a denser distribution of swim routes in the target quadrant.Conclusion Knock-down of TLR2 could inhibit the activation of mi-croglia and its mediated tight junction protein degradation and cerebrovascular barrier network leak-age,and reduce nerve damage in the vascular dementia rat model.