Effect Of Occupational Aluminum Exposure On Tau Protein Phosphorylation In Workers

Objective:To discuss the effect of occupational aluminum exposure on cognitive function and tau protein phosphorylation in workers, and observe the effect of cyclin-dependent kinase 5(CDK), protein phosphatase-2A(PP2A) and ubiquitin-proteasome pathway carboxyl-terminus of Hsp/Hsc70 interacting protein(CHIP) involved in the aluminum-induced tau protein phosphorylation, use survey methods of occupational epidemiology. Methods:A cross sectional study was used to collect a total of 418 male workers from the aluminum plant as research objects. They were divided into three groups according to blood aluminum levels: a low blood aluminum group, a middle aluminum group and a high blood aluminum group. Mini mental state examination(MMSE), digit span(DS), fuld object memory evaluation(FOM), simple reaction time test(SRTT) are used in the investigation of the cognitive situation of these workers. To test blood aluminum content, fasting venous blood samples of the workers were collected and analysed by graphite furnace atomic absorption spectrometry. Enzyme linked immune sorbent assay(ELISA) were used to determine the expression levels of phosphorylated tau181(P-tau181), phosphorylated tau231(P-tau231), CDK5, CHIP, ubiquitin(Ub) and proteasome(PSM) in plasma; Colorimetric quantitative detection kit was used to determine the activity of PP2A; Changes in protein levels between different groups was compared by univariate variance analysis, while using multivariate statistical methods find relevance between blood aluminum levels, phosphorylated tau and cognitive function, correlation in phosphorylated tau and CDK5, PP2 A, CHIP, Ub and PSM expression. Results:1.(1) Occupational aluminum exposed workers were divided into three groups according to P25 å'Œ P75 of the level of plasma aluminum: a low blood aluminum group(64.00±17.78 μg/L), a middle blood aluminum group(132.59±27.45 μg/L) and a high blood aluminum group(244.45±69.86 μg/L). The basic situations of different groups, including age, education degree, seniority, smoking and drinking have no statistical difference.(2) Comparison of cognitive function test: The difference of MMSE(F=6.307, P<0.01), DS(F=3.129, P<0.05), FOM(F=3.194, P<0.05), SRTT(F=3.053, P<0.05) test scores in different groups was statistically significant; Multiple comparisons:compared with the low blood aluminum group, the MMSE scores of the high blood aluminum group and middle blood aluminum group were significantly lower(P<0.05); FOM, DS scores were significantly lower in high blood aluminum group than in low blood aluminum group and middle blood aluminum group(P<0.05); the average reaction time of SRTT test was significantly higher in the high blood aluminum group than in the low blood aluminum group and middle blood group(P<0.05).(3) Comparison of the levels of phosphorylated tau protein: The difference of P-tau181(F=3.627, P<0.05), P-tau231(F=3.177, P<0.05) level in different groups was statistically significant; Multiple comparisons: P-tau181 and P-tau231 levels were significantly higher in high blood aluminum group than in the low blood aluminum group, and the difference was statistically significant(P<0.05).(4) Correlation analysis of plasma aluminum, phosphorylated tau and cognitive function: the level of plasma aluminum was positively correlated with P-tau181(r=0.308, P<0.05), P-tau231(r=0.380, P<0.01), indicating that with the increase of the level of plasma aluminum, P-tau181 and P-tau231 increased; the level of plasma aluminum was negatively correlated with MMSE(r=-0.306, P<0.01) and FOM(r=-0.243, P<0.05), and was positively correlated with SRTT(r=0.262, P<0.05), indicating that with the increase of the level of plasma aluminum, MMSE, FOM test scores decreased, the average reaction time increased; P-tau181 was negatively correlated with MMSE, DS and FOM(r=-0.308,-0.285,-0.252, P<0.05), indicating that with the increase of P-tau181 expression, MMSE, DS and FOM test scores decreased; P-tau231 was negatively correlated with MMSE and DS(r=-0.326,-0.291, P<0.05), and was positively correlated with SRTT(r=0.257, P<0.05), indicating that with the increase of P-tau231 expression, the average reaction time was increased.2.(1) Determination of CDK5 and PP2A: the difference of CDK5(F=3.235, P<0.05), PP2A(F=3.831, P<0.05) expression in different groups was statistically significant; Multiple comparisons: compared with the low blood aluminum group, the expression of CDK5 in the high blood aluminum group and middle blood aluminum group were significantly increased, the difference is statistically significant(P<0.05); the expression of PP2 A in the high blood aluminum group was lower than that of the low and middle blood aluminum group, and the difference was statistically significant(P<0.05).(2) Determination of CHIP, Ub and PSM: the difference of CHIP(F=3.510, P<0.05), Ub(F=3.785, P<0.05), PSM(F=3.496, P<0.05) expression in different groups was statistically significant; Multiple comparisons: compared with the low blood aluminum group, the expression of CHIP, Ub and PSM in the high and middle blood aluminum group were significantly higher, and the difference was statistically significant(P<0.05).(3) Correlation analysis between phosphorylated tau protein and CDK5, PP2 A, CHIP, Ub and PSM: the degree of correlation with P-tau181 was: Ub(0.328) >CDK5(0.327) > CHIP(0.282) > PSM(0.254) > PP2A(-0.247); with P-tau231 was: PP2A(-0.286) > Ub(0.260) > PSM(0.259) > CDK5(0.253) > CHIP(0.245). CDK5, CHIP, Ub, PSM and P-tau181, P-tau231 were positively correlated; PP2 A and P-tau181, P-tau231 were negatively correlated.(4) Multiple stepwise regression analysis: P-tau181 and Ub, CHIP have a linear regression relationship, P-tau231 and PP2 A, PSM have a linear regression relationship, which is negatively correlated with PP2 A, the effect of PP2 A on P-tau231 is greater than that of PSM. Conclusions:1. Occupational aluminum exposure can lead to cognitive impairment and the increased level of tau phosphorylation of workers, and there is a certain correlation between the blood aluminum levels, phosphorylated tau and cognitive function, phosphorylated tau plays an important role in monitoring aluminum-induced cognitive decline;2. The ubiquitin proteasome pathway CHIP involved and PP2 A have effect on aluminum-induced tau phosphorylation.