HMGB1/TLR4 Promotes Apoptosis and Weakens Autophagy of Hippocampal Neurons in Diabetes Combined with OSA

Abstract

Background: Obstructive sleep apnea (OSA) combined with type 2 diabetes (T2DM) may lead to cognitive dysfunction, but the underlying mechanism remain largely unknown. Methods: We performed experiments in mice hippocampal tissues and HT22 cells by immunofluorescence and western blot. Type 2 diabetes model KKAy mice and normal C57BL / 6J mice were exposed to IH or intermittent normoxia. HT22 cells were cultured in high glucose medium and exposed to IH or intermittent normoxia. We then transfected siRNA HMGB1 into HT22 cells then treated with high glucose combined with intermittent hypoxia. Findings: In conclusion, IH aggravated apoptosis and autophagy defects in T2DM mice, and increased protein expression of HMGB1 and TLR4. It was also confirmed in HG combined with IH-treated hippocampal HT22 cells. HMGB1 siRNA can significantly reduce the protein expression of HMGB1 and TLR4, reverse neuronal apoptosis and enhance autophagy. Interpretation: HMGB1-TLR4 signaling regulates autophagy dysfunction and promotes apoptosis in hippocampal neurons of OSA complicated with T2DM. Targeting HMGB1/TLR4 signaling as a novel approach may delay or prevent the increased apoptosis and decreased autophagy induced by T2DM combined with OSA, and ultimately hope to improve cognitive dysfunction. Funding Statement: This work was partly supported by the National Natural Science Foundation of China (81570084 and 81270144 to J.F.), the China Postdoctoral Science Foundation Grant (2015M581309 to B.S.). Declaration of Interests: The author declares that the study does not have any potential conflicts of interest. Ethics Approval Statement: The animal research program follows the Animal Ethics and Use Committee of Tianjin Medical University.