An analysis of vascular factors of Alzheimer′s disease and an experimental intervention of tanshinone Ⅱ A on mouse models of AD / 中华神经医学杂志

ABSTRACT

Objective To evaluate the relationship between Alzheimer′s disease(AD)and its partial vascular risk factors,and investigate the effect of tanshinone ⅡA(Tan ⅡA)on experimental models of AD combined with chronic cerebral ischemia and its potential mechanism.Methods Eight hundred and forty-nine patients with dementia(549 having diagnosis of AD and 300 without AD),admitted to our hospital from 1975 to 2009,were collected in our study; univariate analysis was performed on the relation between AD and vascular risk factors.Besides that,Tg+ mice were employed in our study and randomly divided into 5 groups,namely,sham-operated group,vehicle group,low Tan ⅡA treatment group,medium Tan ⅡA treatment group and high Tan ⅡA treatment group; or these mice were randomly divided into sham-operated group,vehicle group,Tan ⅡA treatment group(treated with 10 mg/kg daily).Mouse models of AD and chronic cerebral ischemia were established,and Tan ⅡA treatment was given to the Tan ⅡA treatment group.The relationship between AD and vascular factors was assessed by means of analyzing the clinicopathological data of AD cohort.The changes of learning and memory abilities in the mouse models were detected by Morris water maze test.Enzyme-linked immuno sorbent assay(ELISA)was employed to detect the level of VEGF; the protein expressions of betaA4-amyloid precursor protein (APP),VEGF and VEGFR-1 were determined by Western blotting,and the mRNA expressions of APP,VEGF and VEGFR-1 were observed by quantitative RT PCR.The effect of Tan ⅡA on canaliculization of human umbilical vein endothelial cells(HUVECs)was also investigated fiom cellular level.Results AD was significantly positively correlated with such vascular risk factors as hypertension,diabetes mellitus,coronary disease,cerebrovascular disease and hyperlipemia(P＜0.05),while no correlation was noted between AD and pneumonia.The mice of the medium Tan ⅡA treatment group and high Tan ⅡA treatment group had obviously shortened times of searching the platform and swimming distance,prolonged latency of avoiding darkness,decreased frequency of wrong behaviors,and decreased level of VEGF as compared with the vehicle group(P＜0.05).The life span in mice of the Tan ⅡA treatment group (treated with 10 mg/kg daily)was prolonged for approximately 24 d as compared with that in the vehicle group; the expressions of APP and VEGF were down-regulated and that of VEGFR-1 in mice of the Tan ⅡA treatment group(treated with 10 mg/kg daily)was up-regulated as compared with those in the vehicle group(P＜0.05).The canaliculization of HUVECs was enhanced after incubation with Tan ⅡA for 48 h,followed by increase of VEGFR-1 expression.Conclusion AD is significantly correlated with its vascular factors.Tan ⅡA could improve the learning and memory abilities of dementia mouse through up-regnlation of VEGFR-1 expression and promotion of vascular integrity,indicating the crucial role of vascular factors in treatment of AD.