Objective To investigate the dynamic changes in phosphorylation levels of tau proteins in the acute,sub-acute and chronic stages after traumatic brain injury (TBI) in mice.Methods Mouse models with moderate TBI were developed using the controlled cortical impactor.Forty specific pathogen free (SPF) male C57BL/6 mice were allocated to TBI group and sham operation group according to the random number table.TBI group was subdivided at 24 hours,7 days,and 1 month.There were 10 mice per group.Levels of tau protein phosphorylation in the brain,gliosis,neuronal loss,and amyloid precursor protein (APP)-labeled axonal injury were detected by immunohistochemistry at 24 hours,7 days,and 1 month after TBI.Results Levels of tau protein phosphorylation in contralateral dentate gyrus at Ser404 site were 4 451.021 ±471.731,5 339.826 ± 794.071,and 1 906.036 ± 369.808 at 24 hours,7 days,and 1 month posttrauma,far higher than 368.630 ±231.038 in sham operation group (t =23.316,18.033,9.979 respectively,P ＜0.01).Whereas,there were no significant differences of tau protein phosphorylation at Ser262 and Thr205 between TBI and sham operation groups at all time points.Immunohistochemical staining for glial fibrous acid protein (GFAP) showed the absorbance value in TBI group was 30 495.233 ± 6 174.094 and 86 427.920 ± 11 896.771 at 24 hours and 7 days,far higher than 6 825.653-± 3 451.641 in sham operation group (t =9.573,9.573 respectively,P ＜ 0.01).Besides,the absorbance value in TBI group was 9 511.471 ± 5 431.077 at 1 month,with no statistical difference in contrast with sham operation group (t =1.181,P ＞ 0.05).Immunohistochemical staining for APP indicated the absorbance value in TBI group was 1 802.695 ± 491.938,2 762.852 ± 636.524,and 2 333.118 ± 511.731 at 24 hours,7 days,and 1 month,higher than 459.061-± 368.608 in sham operation group (t =5.684,7.960,7.697 respectively,P ＜ 0.01).Number of NeuN-labeled neurons in contralateral dentate g3rus revealed no statistical difference between TBI and sham operation groups at 24 hours [(290.056 ±39.162) vs(314.019 ±42.397),t =-1.017,P ＞0.05],but at 7 days and 1 month fewer neurons (250.509 ± 17.592,242.717 ± 17.045) were detected in TBI group than in sham operation group (t =-3.112,-3.506,P ＜ 0.01).Conclusion Persistance hyperphosphorylation of tau protein at Ser404 site may contribute to the cognitive dysfunction in the chronic stage after TBI.