Activation of Sirtuin 1 Attenuates High Glucose-Induced Neuronal Apoptosis by Deacetylating p53.

Xiajie Shi,Zhenqi Liu,Shanlei Zhou,Fangyuan Min,Linhua Pi,Shan Wang,Xin Li,Jing Wu

doi:10.3389/fendo.2018.00274

Abstract

Diabetes mellitus (DM) has been proven to be a key risk factor for cognitive impairment. Previous studies have implicated hippocampal neuronal apoptosis in diabetes-related cognitive impairment. However, the underlying mechanism remains unknown. Sirtuin 1 (SIRT1) is a protein deacetylase depended on nicotinamide adenine dinucleotide. Furthermore, it is indispensable in normal learning and memory. Whether SIRT1 is taken part in diabetes-induced neuronal apoptosis and thus involve in the development of diabetic cognitive impairment is still not clear. To address this issue, we examined the possible role of SIRT1 in hippocampal neuronal apoptosis in streptozotocin-induced diabetic mice. Furthermore, the possible mechanism was investigated in high glucose-induced SH-SY5Y cells. We found that downregulation of the activity and expression of SIRT1 was associated with increased hippocampal neuronal apoptosis in mice. In vitro, cell apoptosis induced by high glucose which was accompanied by a downregulation of SIRT1 and an increased acetylation of p53. On the contrary, activation of SIRT1 using its agonist resveratrol ameliorated cell apoptosis via deacetylating p53. Our data suggest that high concentration of glucose can induce neuronal apoptosis through downregulation of SIRT1 and increased acetylation of p53, which likely contribute to the development of cognitive impairment in diabetes.

Highlights

Diabetes has been characterized as a group of metabolic diseases caused by chronic hyperglycemia
The major aim of our work was to explore whether Sirtuin 1 (SIRT1) is involved in neuronal apoptosis induced by diabetes
Activation of SIRT1 could alleviate high glucose-induced cell apoptosis by deacetylate p53. These findings revealed a novel molecular mechanism involving neuronal apoptosis in diabetes mellitus

Summary

Introduction

Diabetes has been characterized as a group of metabolic diseases caused by chronic hyperglycemia. Numerous epidemic studies have demonstrated that diabetes increases the risk of the development of cognitive impairment [1,2,3]. With the fast growing number of diabetes and the ever-increasing aging people, diabetic-related diabetic cognitive impairment will challenge public health implication in the future. A better insight into the molecular mechanism of the association between diabetes and dementia is of great importance for preventing and slowing the progression of cognitive dysfunction in people with diabetes. Several previous studies have indicated that apoptosis in hippocampal neuron promoted the progression of diabetic cognitive dysfunction [4,5,6,7]. The mechanism of neuronal apoptosis in diabetes is still unclear

Objectives

Methods

Results

Conclusion