Chronic hypoxia leads to cognitive impairment by promoting HIF-2α-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation

Chronic hypoxia leads to irreversible cognitive impairment, primarily due to hippocampal neurodegeneration, for which the underlying mechanism remains poorly understood. We administered hypoxia (13%) to C57BL mice for 1-14 days in this study. Chronic hypoxia for 7 or 14 d, but not 1 or 3 d, resulted in alpha-synuclein hyperphosphorylation at serine129 (alpha-Syn p-S129) and protein aggregation, hippocampal neurodegeneration, and cognitive deficits, whereas the latter could be prevented by alpha-synuclein knockdown or an administered short peptide competing at alpha-Syn S129. These results suggest that alpha-Syn p-S129 mediates hippocampal degeneration and cognitive impairment following chronic hypoxia. Furthermore, we found that chronic hypoxia enhanced ceramide catabolism by inducing hypoxia-inducible factor (HIF)-2 alpha and HIF-2 alpha-dependent transcriptional activation of alkaline ceramidase 2 (Acer2). Thus, the enzymatic activity of protein phosphatase 2A (PP2A), a specific phosphatase for alpha-syn, is inhibited, leading to the sustained induction of alpha-Syn p-S129. Finally, we found that intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing alpha-Syn p-S129. These results proved the critical role of alpha-syn pathology in chronic hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying alpha-syn hyperphosphorylation during chronic hypoxia. The findings bear implications in developing novel therapeutic interventions for chronic hypoxia-related brain disorders.

Automated summary

Chronic hypoxia leads to irreversible cognitive impairment, primarily due to hippocampal neurodegeneration. The underlying mechanism of this process is poorly understood. This study found that chronic hypoxia can induce alpha-synuclein hyperphosphorylation, protein aggregation, hippocampal neurodegeneration, and cognitive deficits. It was also discovered that chronic hypoxia enhances ceramide catabolism, leading to the inhibition of protein phosphatase 2A and sustained induction of alpha-synuclein hyperphosphorylation. Intermittent hypoxic preconditioning can protect against chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing alpha-synuclein hyperphosphorylation. This research reveals a novel mechanism underlying alpha-synuclein pathology during chronic hypoxia and has implications for developing therapeutic interventions for chronic hypoxia-related brain disorders.