DNA binding protein HMGB1 secreted by activated microglia promotes the apoptosis of hippocampal neurons in diabetes complicated with OSA

Type 2 diabetes mellitus (T2DM) complicated with obstructive sleep apnea (OSA) may cause neuronal apoptosis and cognitive deficits, but the underlying mechanisms remain unclear. We aimed to determine the relationship between the activation of microglia and the apoptosis of hippocampal neurons, specifically in terms of high mobility group box-1 (HMGB1), after high glucose (HG) and intermittent hypoxia (IH) exposure. Diabetic KK-Ay mice and non-diabetic C57BL/6J mice (C57 mice) underwent IH or normoxia (control) exposure for 4 weeks. Cognitive function, microglial activation and hippocampal neuronal apoptosis were assessed after IH or normoxia exposure. Compared with C57 control mice, KK-Ay control mice exhibited increased cognitive dysfunction, microglial activation and hippocampal neuronal apoptosis. There were no differences between untreated KK-Ay control mice and C57 mice that had been exposed to IH. The abovementioned responses were aggravated in IH-exposed KK-Ay mice compared with control KK-Ay mice. In vitro, a cellular co-culture experiment showed that HG combined with IH could activate BV2 microglia, leading to the release of neuroinflammatory factors (ROS, TNF-α, IL-1β) and mediating the apoptosis of HT22 cells via the PI3K/Akt/GSK-3β signaling pathway. Meanwhile, HMGB1 was actively secreted into the extracellular environment from activated BV2 microglia. As a proinflammatory factor, it was able to sustain microglial activation by directly acting on those cells. The activation promoted positive feedback and aggravated neuronal damage further. In a cellular monoculture or co-culture system, HMGB1 siRNA was able to alleviate the activation of BV2 cells and the apoptosis of HT22 cells induced by HG combined with IH. Our object is to show that inhibition of HMGB1 may break the vicious cycle to prevent or treat neuroinflammation and hippocampal neuronal apoptosis caused by T2DM complicated with OSA.