Objective:To investigate the effects of insulin resistance induced by long-term high-fat diet on cognitive function and brain phosphorylated Tau protein in pR5 MAPT Tau transgenic mice.Methods:Eight-week-old female pR5 MAPT transgenic mice were divided into standard diet(STD) group (pR5 STD, n=8) and high-fat diet(HFD) group (pR5 HFD, n=8). Female wild-type C57BL/6 mice fed with STD were used as control group (WT STD, n=8). The experiment was carried out for 30 weeks until the mice were old.During the experiment, the weight of mice was measured once a week and fasting blood glucose was measured once every two weeks.Thirty weeks later, glucose tolerance test and insulin tolerance test were carried out.Forced swimming test and tail suspension test were used to evaluate the depressive behavior of mice, and elevated plus maze test was used to evaluate the anxiety behavior, Morris water maze test was used to evaluate spatial memory behavior.The levels of total Tau protein and phosphorylated Tau proteins H7-tau, p-tau-Ser396 and p-tau-Thr231 were detected by Western blot.SPSS 17.0 software was used for statistical analysis, repeated measurement ANOVA was used for the data of glucose tolerance test and insulin tolerance test, one-way ANOVA was used for multi group comparison, and LSD test was used for further pairwise comparison. Results:After 30 weeks of high-fat diet, there were significant differences in body weight and fasting blood glucose among the three groups ( F=808.31, 1 117.18, both P<0.01). The body weight of mice in pR5 HFD group ((54.35±2.52)g) was higher than those in pR5 STD group ((24.95±1.15) g) and WT STD group ((23.86±1.10) g) (both P<0.01), and the fasting blood glucose of mice in pR5 HFD group ((8.12±0.24) mmol/L) was significantly higher than those in pR5 STD group ((4.64±0.13) mmol/L) and WT STD group ((4.45±0.22) mmol/L) (both P<0.01). Glucose tolerance test showed that within 120 minutes after injection of glucose, there was a significant time and group interaction in the blood glucose value among the three groups ( F=113.30, P<0.01). After glucose injection, the peak value of blood glucose in pR5 HFD group was delayed, suggesting that glucose tolerance in pR5 HFD group was impaired.The insulin tolerance test showed that there was a significant interaction between time and group in the insulin tolerance among the three groups ( F=209.92, P<0.01). After injection of insulin, the blood glucose in pR5 HFD group decreased slowly, reaching the valley value at 60 min, and then the blood glucose increased significantly, suggesting that the sensitivity of pR5 HFD group mice to insulin decreased significantly.There were significant differences in the percentage of forced swimming immobility time and tail suspension immobility time among the three groups ( F=37.05, 59.29, both P<0.01). The two indexes of pR5 STD group and pR5 HFD group were both higher than those of WT STD group (all P<0.01), and those of pR5 HFD group were both higher than those of pR5 STD group (both P<0.01). The results of elevated plus maze showed that there were significant differences in the activity distance and time in open arm among the three groups ( F=7.82, 10.37, both P<0.05) .The activity distance ((0.40±0.21) m) and activity time ((27.38±8.80) s) of pR5 HFD group were significantly lower than those of pR5 STD group ((2.31±1.74) m, (63.56±27.52)s) (both P<0.05). The space exploration test showed that the residence time in the target quadrant of pR5 HFD group ((15.56±1.16)s) was less than that of pR5 STD group((19.18±0.64)s)( P<0.01), and the time of entering the platform area of pR5 HFD group((1.43±0.06)s) was less than that of pR5 STD group((1.66±0.12)s)( P<0.01). Western blot showed that there were significant differences in the levels of total Tau protein, H7-tau, p-tau-Ser396 and p-tau-Thr231 protein among the three groups ( F=101.50, 80.60, 55.47, 30.89, all P<0.05). Further pairwise comparison showed that the levels of the four Tau proteins showed: the levels of the proteins in pR5 STD group and pR5 HFD group were all higher than those of WT STD group (all P<0.01), and those in pR5 HFD group were all higher than those in pR5 STD group (all P<0.05). Conclusion:Long-term high fat diet causes obesity, hyperglycemia and peripheral insulin resistance, and promotes the cognitive impairment of MAPT mice, which is related to the increase of Tau protein phosphorylation in the brains of MAPT mice.