Sirt1 Mediated High-Glucose-Induced Aβ Deposition and Cognitive Impairment through Activation of the TLR9/p53 Pathway

Background: Diabetic encephalopathy (DE) is a chronic central nervous system complication caused by diabetes mellitus (DM). β-amyloid (Aβ) deposition has been considered as the main cause of cognitive impairment in DE. Previous researches concerned the effect of canonical TLR9/Myd88 inflammatory pathway. However our study explored the function of non-inflammatory pathway of Toll-like receptor 9 (TLR9), acting on Sirt1 to influence Aβ deposition and cognitive function in DE. Results: : We found that, compared with DM mice, TLR9 -/- DM mice performed better learning ability and short-term memory, along with lower Aβ in hippocampi, but could be reversed by Sirt1 inhabition. 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 reduction or cognitive improvement, were altered (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 the diagnosis and treatment of DE.