ArticleCell death discovery2022
Chronic hypoxia leads to cognitive impairment by promoting HIF-2α-mediated ceramide catabolism and alpha-synuclein hyperphosphorylation.
Article in Cell death discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- G Protein-Coupled Receptor in High-Altitude Diseases: Mechanistic Insights and Therapeutic Opportunities.MedComm · 2026Review
- Targeting mTOR to Mitigate Sequelae of Chronic Hypoxia on the Carotid Artery and Cerebral Circulation.Comprehensive Physiology · 2026Article
- High-Altitude Hypoxia Activates JNK-p53 Signaling: Linking Hippocampal Energy Crisis to Cognitive Impairment.CNS neuroscience & therapeutics · 2026Article
- X-Linked USP11 Drives Depression-Like Behaviors by Stabilizing CK2α and Disrupting Mitochondrial Function.CNS neuroscience & therapeutics · 2026Article
- A hypoxia-sensitive medullary nucleus modulates cerebral blood flow via a disynaptic pathway to cortex.bioRxiv : the preprint server for biology · 2026Article
- Chronic intermittent hypoxia increases Parkinson's disease susceptibility via PPARα-mediated lipid droplet-mitochondrial dysfunction.Theranostics · 2026Article
- Neurovascular Signaling at the Gliovascular Interface: From Flow Regulation to Cognitive Energy Coupling.International journal of molecular sciences · 2025Review
- Brain endothelial HIF-1Acta pharmaceutica Sinica. B · 2025Article
- Molecular mechanisms of α-syn abnormal phase separation in cognitive impairment induced by chronic intermittent hypoxia and the neuroprotective effects of Danshensu methyl ester.Molecular medicine (Cambridge, Mass.) · 2025Article
- Inhibition of the HMGB1-RAGE Axis Attenuates Microglial Inflammation and Ameliorates Hypoxia-Induced Cognitive Impairment.International journal of molecular sciences · 2025Article
- Exploring the role of HIF-1α in pathogenesis of parkinson's disease and its potential as a therapeutic target.Molecular biology reports · 2025Review
- Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.eLife · 2025Article
- Hypoxia's Impact on Hippocampal Functional Connectivity: Insights from Resting-State fMRI Studies.Brain sciences · 2025Review
- Electroacupuncture mitigates cognitive impairments in chronic hypoxia-induced mice by modulating neuroinflammation.IBRO neuroscience reports · 2025Article
- Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.Basic research in cardiology · 2025Article
- Chronic Intermittent Hypoxia-Induced Neural Injury: Pathophysiology, Neurodegenerative Implications, and Therapeutic Insights.CNS neuroscience & therapeutics · 2025Review
- Genome-wide and phenome-wide studies provided insights into brain glymphatic system function and its clinical associations.Science advances · 2025Article
- Curcumin reverses cognitive deficits through promoting neurogenesis and synapse plasticity via the upregulation of PSD95 and BDNF in mice.Scientific reports · 2025Article
- Vagus nerve stimulation ameliorates cognitive impairment caused by hypoxia.Frontiers in behavioral neuroscience · 2025Article
- Spiral volumetric optoacoustic tomography of reduced oxygen saturation in the spinal cord of M83 mouse model of Parkinson's disease.European journal of nuclear medicine and molecular imaging · 2025Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
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 (α-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 α-Syn S129. These results suggest that α-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)-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 the sustained induction of α-Syn p-S129. Finally, we found that intermittent hypoxic preconditioning protected against subsequent chronic hypoxia-induced hippocampal neurodegeneration and cognitive impairment by preventing α-Syn p-S129. These results proved the critical role of α-syn pathology in chronic hypoxia-afforded cognitive impairment and revealed a novel mechanism underlying α-syn hyperphosphorylation during chronic hypoxia. The findings bear implications in developing novel therapeutic interventions for chronic hypoxia-related brain disorders.
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