Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly ...Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the healthrelated quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription(Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat(1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat_(1–72) was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat_(1–72)(0–6 h) modulates protein phosphatase 1(PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat_(1–72)(24 h) downregulates CREB activity and CREBmediated gene(BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat_(1–72) might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.展开更多
基金supported by Grants from the National Natural Science Foundation of China (81571987)
文摘Despite the success of combined antiretroviral therapy in recent years, the prevalence of human immunodeficiency virus(HIV)-associated neurocognitive disorders in people living with HIV-1 is increasing, significantly reducing the healthrelated quality of their lives. Although neurons cannot be infected by HIV-1, shed viral proteins such as transactivator of transcription(Tat) can cause dendritic damage. However, the detailed molecular mechanism of Tat-induced neuronal impairment remains unknown. In this study, we first showed that recombinant Tat(1–72 aa) induced neurotoxicity in primary cultured mouse neurons. Second, exposure to Tat_(1–72) was shown to reduce the length and number of dendrites in cultured neurons. Third, Tat_(1–72)(0–6 h) modulates protein phosphatase 1(PP1) expression and enhances its activity by decreasing the phosphorylation level of PP1 at Thr320. Finally, Tat_(1–72)(24 h) downregulates CREB activity and CREBmediated gene(BDNF, c-fos, Egr-1) expression. Together, these findings suggest that Tat_(1–72) might impair cognitive function by regulating the activity of PP1 and the CREB/BDNF pathway.
