神経学的障害

Sirt1 Mediated High-Glucose Induced AΒ Deposition and Cognitive Impairment through Activation of the TLR9/P53 Pathway

Abstract

Yue Sun1 , Shiyu Zhu1, Jinliang Chen1, Yuxing Zhao1, Cheng Luo1, Lv Qiong1, Zhiyin Liao1, Kexiang Zhao1, Yuan Gao1, DiWang2 and Qian Xiao1*

Aim: DE is a chronic central nervous system complication caused by DM. Aβ^² deposition has been considered as the main cause of cognitive impairment in DE. Our study explored the function of non-inflammatory pathway of TLR9, that acting on Sirt1 related Aβ² deposition and cognitive function in DE.

Methods: Wide type and TLR9 knockout C57BL/6J mice were randomly divided into a control and a DM group. The DM rat was produced by intraperitoneal injection of STZ. And adeno associated virus was injected into their hippocampi to inhibit Sirt1. 12 weeks later, the rats were tested in water maze and then sacrificed. Hippocampi were for immunohistochemistry, Western blot, and RT-PCR. In vitro HT22 cells were incubated with or without high glucose medium and further intervened with TLR9 antagonist ODN2088 and p53 over expressed lent viral infection. The detection method was almost the same as in vivo, except for flow cytometry.

Results: We found that, compared with DM mice, TLR9-/-DM mice performed better in learning ability and short term memory and contained lower Aβ², but could be reversed by Sirt1 inhibition. Furthermore, in vitro, after intervention with high glucose and p53 over expressed lentiviral infection, we observed the positive results of TLR9 inhibition, such as Sirt1 up regulation, Aβ^² reduction or cognitive improvement, were reversed (all P<0.05).

Conclusions: We considered that TLR9/p53/Sirt1 signalling pathway induced by high glucose are one of molecular mechanisms underlying DE. These results not only confirm the importance of blood glucose management but also provide new insights for treatment of DE.