Chronic hypoxia leads to cognitive impairment by promoting HIF-2 alpha -mediated alpha-synuclein hyperphosphorylation

Abstract Background: Cognitive impairment is involved in various central nervous system diseases. Hypoxia is a critical common factor that induces cognitive impairment, but its specific molecular mechanism remains unclear. Understanding the mechanism of cognitive impairment induced by hypoxia will provide potential molecular targets for the intervention of cognitive disorders.Methods: We used hypoxic chambers to establish a chronic hypoxic model in mice. Cognitive impairment, hippocampal neurodegeneration, and alpha-synuclein (α-syn) pathology were assessed in these mice. The α-syn knockout mice or mice administered a competing peptide targeting serine 129 (ser129) were used to investigate the role and molecular mechanism of α-syn pathology in chronic hypoxia-induced cognitive impairment. Finally, we investigated the protective role of intermittent hypoxia preconditioning in chronic hypoxia-induced α-syn pathology and cognitive impairment.Results: Chronic hypoxia resulted in α-syn hyperphosphorylation at ser129 and protein aggregation, hippocampal neurodegeneration, and irreversible cognitive deficits. The latter could be reversed by α-syn knockdown or an administered short peptide competing at α-syn ser129. These results suggest that α-syn hyperphosphorylation at ser129 mediates hippocampal degeneration and cognitive impairment following chronic hypoxia. Furthermore, we found that chronic hypoxia enhanced ceramide catabolism by inducing hypoxia-inducible factor (HIF)-2α and HIF-2α-dependent transcriptional activation of alkaline ceramidase 2 (Acer2). Thus, the enzymatic activity of protein phosphatase 2A (PP2A), a specific phosphatase for α-syn, is inhibited, leading to sustained induction of α-syn hyperphosphorylation and aggregation. Finally, we found that enhancing hypoxia tolerance through intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing α-syn pathology. Conclusion: These results proved the critical role of α-syn pathology in hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying hypoxic-specific induction of cognitive impairment. The findings bear implications in developing novel therapeutic interventions for hypoxia-related cognitive disorders.