Hypoxia, sleep architecture, and brain clearance: Converging pathways in neurodegenerative disease
Hypoxia is a fundamental biological stressor that profoundly alters neural function, sleep architecture, and metabolic homeostasis. Emerging evidence indicates that sleep is a critical regulator of glymphatic clearance, the perivascular cerebrospinal fluid exchange system responsible for removing metabolic waste products, such as amyloid-β and tau, from the brain. Disruption of oxygen homeostasis, whether acute, chronic, or intermittent, modifies sleep structure, alters astroglial physiology, and activates hypoxia-responsive signaling pathways that may impair glymphatic efficiency. This review synthesizes current knowledge on the bidirectional relationship between hypoxia and sleep, focusing on molecular mediators such as hypoxia-inducible factors, inflammatory cascades, oxidative stress, and aquaporin-4 polarization. We examine how hypoxia-induced sleep fragmentation and locus coeruleus-mediated noradrenergic arousal compromise brain clearance mechanisms, potentially accelerating neurodegenerative processes associated with Alzheimer’s disease and Parkinson’s disease. Clinical contexts such as obstructive sleep apnea, high-altitude exposure, and cardiopulmonary disorders are discussed as translational models of hypoxia-driven glymphatic dysfunction. Finally, we highlight therapeutic perspectives, including oxygen modulation strategies and pharmacologic manipulation of hypoxia signaling pathways. Understanding how hypoxia reshapes sleep-dependent clearance systems may reveal novel targets to mitigate neurodegenerative disease progression.
Abbott, N. J., Pizzo, M. E., Preston, J. E., Janigro, D., & Thorne, R. G. (2018). The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathologica, 135(3), 387–407. https://doi.org/10.1007/s00401-018-1812-4
Adamovich, Y., Ladeuix, B., Golik, M., Koeners, M. P., & Asher, G. (2017). Rhythmic Oxygen Levels Reset Circadian Clocks through HIF1α. Cell Metabolism, 25(1), 93–101. https://doi.org/10.1016/j.cmet.2016.09.014
Ainslie, P. N., Lucas, S. J., & Burgess, K. R. (2013). Breathing and sleep at high altitude. Respiratory Physiology & Neurobiology, 188(3), 233–256. https://doi.org/10.1016/j.resp.2013.05.020
Alemán-Villa, K. M., Armienta-Rojas, D. A., Camberos-Barraza, J., Rábago-Monzón, Á. R., Camacho-Zamora, A., Osuna- Ramos, J. F., Magaña-Gómez, J. A., Guadrón-Llanos, A. M., Calderón-Zamora, L., Norzagaray-Valenzuela, C. D., Valdez- Flores, M. A., Picos-Cárdenas, V. J., & De La Herrán-Arita, A. K. (2025). Neuroinflammation across the Spectrum of Neurodegenerative Diseases: Mechanisms and Therapeutic Frontiers. Neuroimmunomodulation, 32(1), 278–305. https://doi.org/10.1159/000548021
Alshammari, F., Keil, S. A., & Wilcox, M. E. (2026). Sleep fragmentation, impaired glymphatic clearance, and long-term cognitive impairment after critical illness. Critical Care Science, 38. https://doi.org/10.62675/2965-2774.20260042
Antila, H., Jalonen, S. C., Persson, N. D. Å., Peltoniemi, M., Lohela, T. J., & Lilius, T. O. (2026). Peripheral alpha-2 antagonist vatinoxan improves dexmedetomidine-induced perivascular cerebrospinal fluid flow without affecting electroencephalogram activity in female rats. Neuropharmacology, 287, 110828. https://doi.org/10.1016/j.neuropharm.2026.110828
Arnaud, C., Bochaton, T., Pépin, J., & Belaidi, E. (2020). Obstructive sleep apnoea and cardiovascular consequences: Pathophysiological mechanisms. Archives of Cardiovascular Diseases, 113(5), 350–358. https://doi.org/10.1016/j.acvd.2020.01.003
Aston-Jones, G., & Cohen, J. D. (2005). AN INTEGRATIVE THEORY OF LOCUS COERULEUS-NOREPINEPHRINE FUNCTION: Adaptive gain and optimal performance. Annual Review of Neuroscience, 28(1), 403–450.
https://doi.org/10.1146/annurev.neuro.28.061604.135709
Badaut, J., Ashwal, S., Adami, A., Tone, B., Recker, R., Spagnoli, D., Ternon, B., & Obenaus, A. (2010). Brain Water Mobility Decreases after Astrocytic Aquaporin-4 Inhibition Using RNA Interference. Journal of Cerebral Blood Flow & Metabolism, 31(3), 819–831. https://doi.org/10.1038/jcbfm.2010.163
Benveniste, H., Liu, X., Koundal, S., Sanggaard, S., Lee, H., & Wardlaw, J. (2018). The Glymphatic System and Waste Clearance with Brain Aging: A Review. Gerontology, 65(2), 106–119. https://doi.org/10.1159/000490349
Bloch, K. E., Buenzli, J. C., Latshang, T. D., & Ulrich, S. (2015). Sleep at high altitude: guesses and facts. Journal of Applied Physiology, 119(12), 1466–1480. https://doi.org/10.1152/japplphysiol.00448.2015
Buccellato, F. R., D’Anca, M., Serpente, M., Arighi, A., & Galimberti, D. (2022). The role of glymphatic system in Alzheimer’s and Parkinson’s disease pathogenesis. Biomedicines, 10(9), 2261. https://doi.org/10.3390/biomedicines10092261
Camberos-Barraza, J., Alemán-Villa, K. M., & De La Herrán- Arita, A. K. (2025). The mind awake at night: Glymphatic dysfunction as a mechanistic bridge linking multifactorial sleep disturbances to neurodegeneration. Journal of Clinical and Basic Psychosomatics, 0(0), 025390076. https://doi.org/10.36922/jcbp025390076
Chen, N., Hao, C., Peng, X., Lin, H., Yin, A., Hao, L., Tao, Y., Liang, X., Liu, Z., Xing, C., Chen, J., Luo, L., Zuo, L., Liao, Y., Liu, B., Leong, R., Wang, C., Liu, C., Neff, T., . . . Yu, K. P. (2019). Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. New England Journal of Medicine, 381(11), 1001–1010. https://doi.org/10.1056/nejmoa1813599
Chen, X., Tamang, S. M., Du, F., & Ongur, D. (2019). Glutamate diffusion in the rat brain in vivo under light and deep anesthesia conditions. Magnetic Resonance in Medicine, 82(1), 84–94. https://doi.org/10.1002/mrm.27722
Coleman, M. L., & Ratcliffe, P. J. (2007). Oxygen sensing and hypoxia-induced responses. Essays in Biochemistry, 43, 1–16. https://doi.org/10.1042/bse0430001
Dagum, P., Giovangrandi, L., Levendovszky, S. R., Winebaum, J. J., Singh, T., Cho, Y., Kaplan, R. M., Jaffee, M. S., Lim, M. M., Vandeweerd, C., & Iliff, J. J. (2025). A wireless device for continuous measurement of brain parenchymal resistance tracks glymphatic function in humans. Nature Biomedical Engineering, 9(10), 1656–1676. https://doi.org/10.1038/s41551-025-01394-9
Daulatzai M. A. (2013). Death by a thousand cuts in Alzheimer’s disease: hypoxia--the prodrome. Neurotoxicity Research, 24(2), 216–243. https://doi.org/10.1007/s12640-013-9379-2
De La Herrán-Arita, A. K. (2025). When sleep fails, brain clearance suffers: the role of glymphatic impairment in clinical neurology. Acta Neurologica Belgica. https://doi.org/10.1007/s13760-025-02959-w
Delaney, L., & Elliott, R. (2025). Sleep disturbance in ICU: A pathway to delirium. Intensive and Critical Care Nursing, 90, 104138. https://doi.org/10.1016/j.iccn.2025.104138
Di Giulio, C., Bianchi, G., Cacchio, M., Artese, L., Rapino, C., Macrì, M. A., & Di Ilio, C. (2005). Oxygen and life span: chronic hypoxia as a model for studying HIF-1α, VEGF and NOS during aging. Respiratory Physiology & Neurobiology, 147(1), 31–38. https://doi.org/10.1016/j.resp.2005.01.006
Ding, F., O’Donnell, J., Xu, Q., Kang, N., Goldman, N., & Nedergaard, M. (2016). Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science, 352(6285), 550–555. https://doi.org/10.1126/science.aad4821
Divecha, Y. A., Rampes, S., Tromp, S., Boyanova, S. T., Fleckney, A., Fidanboylu, M., & Thomas, S. A. (2025). The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player. Pharmacological Reviews, 77(3), 100052. https://doi.org/10.1016/j.pharmr.2025.100052
Douglas, N. J. (1995). The sleep apnoea/hypopnoea syndrome. European Journal of Clinical Investigation, 25(5), 285–290. https://doi.org/10.1111/j.1365-2362.1995.tb01703.x
Efrati, S., & Ben-Jacob, E. (2014). Reflections on the neurotherapeutic effects of hyperbaric oxygen. Expert Review of Neurotherapeutics, 14(3), 233–236. https://doi.org/10.1586/14737175.2014.884928
Fraser, G. L., Riker, R. R., & Coursin, D. C. (2014). Long-Term Cognitive Impairment after Critical Illness. New England Journal of Medicine, 370(2), 184–186. https://doi.org/10.1056/nejmc1313886
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, B. R., Polimeni, J. R., & Lewis, L. D. (2019). Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep. Science, 366(6465), 628–631. https://doi.org/10.1126/science.aax5440
Girouard, H., Bonev, A. D., Hannah, R. M., Meredith, A., Aldrich, R. W., & Nelson, M. T. (2010). Astrocytic endfoot Ca 2+ and BK channels determine both arteriolar dilation and constriction. Proceedings of the National Academy of Sciences, 107(8), 3811–3816. https://doi.org/10.1073/pnas.0914722107
Gottlieb, D. J., Punjabi, N. M., Mehra, R., Patel, S. R., Quan, S. F., Babineau, D. C., Tracy, R. P., Rueschman, M., Blumenthal, R. S., Lewis, E. F., Bhatt, D. L., & Redline, S. (2014). CPAP versus Oxygen in Obstructive Sleep Apnea. New England Journal of Medicine, 370(24), 2276–2285. https://doi.org/10.1056/nejmoa1306766
Hablitz, L. M., Plá, V., Giannetto, M., Vinitsky, H. S., Stæger, F. F., Metcalfe, T., Nguyen, R., Benrais, A., & Nedergaard, M. (2020). Circadian control of brain glymphatic and lymphatic fluid flow. Nature Communications, 11(1). https://doi.org/10.1038/s41467-020-18115-2
Harrison, I. F., Ismail, O., Machhada, A., Colgan, N., Ohene, Y., Nahavandi, P., Ahmed, Z., Fisher, A., Meftah, S., Murray, T. K., Ottersen, O. P., Nagelhus, E. A., O’Neill, M. J., Wells, J. A., & Lythgoe, M. F. (2020). Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model. Brain, 143(8), 2576–2593. https://doi.org/10.1093/brain/awaa179
Harten, S. K., Ashcroft, M., & Maxwell, P. H. (2010). Prolyl hydroxylase domain inhibitors: a route to HIF activation and neuroprotection. Antioxidants and Redox Signaling, 12(4), 459–480. https://doi.org/10.1089/ars.2009.2870
He, R., Zhang, X., Pang, C., Lin, L., Li, S., Jin, L., Ding, L., & Wang, W. (2023). Inhibition of NADPH oxidase 2 improves cognitive abilities by modulating aquaporin-4 after traumatic brain injury in mice. Heliyon, 9(11), e22035. https://doi.org/10.1016/j.heliyon.2023.e22035
Huang, Q., Yang, Y., Ma, H., Yan, X., Wang, Y., Su, J., & Zhang, Q. (2025). Disturbed neurovascular coupling of limbic system in obstructive sleep apnea patients with mild cognitive impairment: A combined fMRI and ASL study. Neuroscience, 581, 104–113. https://doi.org/10.1016/j.neuroscience.2025.06.013
Hussain, R., Tithof, J., Wang, W., Cheetham-West, A., Song, W., Peng, W., Sigurdsson, B., Kim, D., Sun, Q., Peng, S., Plá, V., Kelley, D. H., Hirase, H., Castorena-Gonzalez, J. A., Weikop, P., Goldman, S. A., Davis, M. J., & Nedergaard, M. (2023). Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema. Nature, 623(7989), 992–1000. https://doi.org/10.1038/s41586-023-06737-7
Iadecola, C. (2017). The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron, 96(1), 17–42. https://doi.org/10.1016/j.neuron.2017.07.030
Iliff, J. J., Chen, M. J., Plog, B. A., Zeppenfeld, D. M., Soltero, M., Yang, L., Singh, I., Deane, R., & Nedergaard, M. (2014). Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury. Journal of Neuroscience, 34(49), 16180–16193. https://doi.org/10.1523/jneurosci.3020-14.2014
Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., Nagelhus, E. A., & Nedergaard, M. (2012). A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science Translational Medicine, 4(147). https://doi.org/10.1126/scitranslmed.3003748
Iliff, J. J., Wang, M., Zeppenfeld, D. M., Venkataraman, A., Plog, B. A., Liao, Y., Deane, R., & Nedergaard, M. (2013). Cerebral arterial pulsation drives paravascular CSF–Interstitial fluid exchange in the murine brain. Journal of Neuroscience, 33(46), 18190–18199. https://doi.org/10.1523/jneurosci.1592-13.2013
Iturriaga, R., Del Rio, R., & Alcayaga, J. (2022). Carotid body inflammation: role in hypoxia and in the anti-inflammatory reflex. Physiology, 37(3), 128–140. https://doi.org/10.1152/physiol.00031.2021
Jessen, N. A., Munk, A. S. F., Lundgaard, I., & Nedergaard, M. (2015). The Glymphatic System: A Beginner’s Guide. Neurochemical Research, 40(12), 2583–2599. https://doi.org/10.1007/s11064-015-1581-6
Ju, Y. E. S., McLeland, J. S., Toedebusch, C. D., Xiong, C., Fagan, A. M., Duntley, S. P., Morris, J. C., & Holtzman, D. M. (2013). Sleep quality and preclinical Alzheimer disease. JAMA Neurology, 70(5), 587. https://doi.org/10.1001/jamaneurol.2013.2334
Kashyap, S., Brazdzionis, J., Savla, P., Berry, J. A., Farr, S., Patchana, T., Majeed, G., Ghanchi, H., Bowen, I., Wacker, M. R., & Miulli, D. E. (2021). Osteopathic manipulative treatment to optimize the glymphatic environment in severe traumatic brain injury measured with optic nerve sheath diameter, intracranial pressure monitoring, and neurological pupil index. Cureus. https://doi.org/10.7759/cureus.13823
Kaur, C., Rathnasamy, G., & Ling, E. (2012). Roles of activated microglia in hypoxia induced neuroinflammation in the developing brain and the retina. Journal of Neuroimmune Pharmacology, 8(1), 66–78. https://doi.org/10.1007/s11481-012-9347-2
Kedarasetti, R. T., Drew, P. J., & Costanzo, F. (2020). Arterial pulsations drive oscillatory flow of CSF but not directional pumping. Scientific Reports, 10(1). https://doi.org/10.1038/s41598-020-66887-w
Kimelberg, H. K. (2005). Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia, 50(4), 389–397. https://doi.org/10.1002/glia.20174
Kiviniemi, V., Wang, X., Korhonen, V., Keinänen, T., Tuovinen, T., Autio, J., LeVan, P., Keilholz, S., Zang, Y., Hennig, J., & Nedergaard, M. (2015). Ultra-fast magnetic resonance encephalography of physiological brain activity – Glymphatic pulsation mechanisms? Journal of Cerebral Blood Flow & Metabolism, 36(6), 1033–1045. https://doi.org/10.1177/0271678x15622047
Kosasih, A. M., Chong, Y. F., Lee, P., Zhou, J. H., Lim, D. C., & Lee, C. (2026). Sleep apnea and the ageing brain: bridging mechanisms and clinical outcomes. The American Journal of Medicine. https://doi.org/10.1016/j.amjmed.2026.05.038
Kritsilis, M., Vanherle, L., Rosenholm, M., Zandt, R. I. ‘., Yao, Y., Swanberg, K. M., Weikop, P., Gottschalk, M., Shanbhag, N. C., Luo, J., Boster, K., Nedergaard, M., Meissner, A., & Lundgaard, I. (2024). Loss of glymphatic homeostasis in heart failure. Brain, 148(3), 985–1000. https://doi.org/10.1093/brain/awae411
Kumar, G. K., Peng, Y., Nanduri, J., & Prabhakar, N. R. (2015). Carotid body chemoreflex mediates intermittent Hypoxia- Induced oxidative stress in the adrenal medulla. In Advances in Experimental Medicine and Biology (pp. 195–199). Springer International Publishing. https://doi.org/10.1007/978-3-319-18440-1_21
Lee, H., Xie, L., Yu, M., Kang, H., Feng, T., Deane, R., Logan, J., Nedergaard, M., & Benveniste, H. (2015). The effect of body posture on brain glymphatic transport. Journal of Neuroscience, 35(31), 11034–11044. https://doi.org/10.1523/jneurosci.1625-15.2015
Lim, A. S. P., Kowgier, M., Yu, L., Buchman, A. S., & Bennett, D. A. (2013). Sleep fragmentation and the risk of incident Alzheimer’s disease and cognitive decline in older persons. Sleep, 36(7), 1027–1032. https://doi.org/10.5665/sleep.2802
Massussi, M., Bellicini, M. G., Adamo, M., Pilotto, A., Metra, M., Padovani, A., & Proietti, R. (2024). Connecting the Dots: A narrative review of the relationship between heart failure and cognitive impairment. ESC Heart Failure, 12(2), 1119–1131. https://doi.org/10.1002/ehf2.15144
Meliante, P. G., Zoccali, F., Cascone, F., Di Stefano, V., Greco, A., De Vincentiis, M., Petrella, C., Fiore, M., Minni, A., & Barbato, C. (2023). Molecular pathology, oxidative stress, and biomarkers in obstructive sleep apnea. International Journal of Molecular Sciences, 24(6), 5478. https://doi.org/10.3390/ijms24065478
Mestre, H., Tithof, J., Du, T., Song, W., Peng, W., Sweeney, A. M., Olveda, G., Thomas, J. H., Nedergaard, M., & Kelley, D. H. (2018). Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-07318-3
Mitchell, H. A., & Weinshenker, D. (2009). Good night and good luck: Norepinephrine in sleep pharmacology. Biochemical Pharmacology, 79(6), 801–809. https://doi.org/10.1016/j.bcp.2009.10.004
Mortensen, K. N., Sanggaard, S., Mestre, H., Lee, H., Kostrikov, S., Xavier, A. L., Gjedde, A., Benveniste, H., & Nedergaard, M. (2019). Impaired glymphatic transport in spontaneously hypertensive rats. Journal of Neuroscience, 39(32), 6365–6377. https://doi.org/10.1523/jneurosci.1974-18.2019
Mullins, A. E., Kam, K., Parekh, A., Bubu, O. M., Osorio, R. S., & Varga, A. W. (2020). Obstructive Sleep Apnea and Its Treatment in Aging: Effects on Alzheimer’s disease Biomarkers, Cognition, Brain Structure and Neurophysiology. Neurobiology of Disease, 145, 105054. https://doi.org/10.1016/j.nbd.2020.105054
Naganawa, S., Taoka, T., Ito, R., & Kawamura, M. (2023). The glymphatic system in humans: Investigations with magnetic resonance imaging. Investigative Radiology, 59(1), 1–12. https://doi.org/10.1097/rli.0000000000000969
Nagelhus, E. A., & Ottersen, O. P. (2013). Physiological roles of aquaporin-4 in brain. Physiological Reviews, 93(4), 1543–1562. https://doi.org/10.1152/physrev.00011.2013
Nedergaard, M. (2013). Garbage truck of the brain. Science, 340(6140), 1529–1530. https://doi.org/10.1126/science.1240514
Nelson, L. E., Guo, T. Z., Lu, J., Saper, C. B., Franks, N. P., & Maze, M. (2002). The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway. Nature Neuroscience, 5(10), 979–984. https://doi.org/10.1038/nn913
Nielsen, S., Nagelhus, E. A., Amiry-Moghaddam, M., Bourque, C., Agre, P., & Ottersen, O. P. (1997). Specialized membrane domains for water transport in glial cells: High-Resolution Immunogold Cytochemistry of aquaporin-4 in rat brain. Journal of Neuroscience, 17(1), 171–180. https://doi.org/10.1523/jneurosci.17-01-00171.1997
Nozaleda, G. L., Coenen, W., Haughton, V., & Sánchez, A. L. (2025). Arterial pulsations and transmantle pressure synergetically drive glymphatic flow. Scientific Reports, 15(1). https://doi.org/10.1038/s41598-025-97631-x
Ollonen, T., Kurkela, M., Laitakari, A., Sakko, S., Koivisto, H., Myllyharju, J., Tanila, H., Serpi, R., & Koivunen, P. (2022). Activation of the hypoxia response protects mice from amyloid-β accumulation. Cellular and Molecular Life Sciences, 79(8). https://doi.org/10.1007/s00018-022-04460-6
Oo, T. F., Henchcliffe, C., & Burke, R. E. (1995). Apoptosis in substantia nigra following developmental hypoxic-ischemic injury. Neuroscience, 69(3), 893–901. https://doi.org/10.1016/0306-4522(95)00282-n
Ozkaya, K. S., & Browning, K. N. (2026). The Brain‐Gut axis in Parkinson’s disease pathology. Comprehensive Physiology, 16(2). https://doi.org/10.1002/cph4.70137
Pagel, J. F. (2024). The persistent paradox of rapid eye movement sleep (REMS): brain waves and dreaming. Brain Sciences, 14(7), 622. https://doi.org/10.3390/brainsci14070622
Papalambros, N. A., Santostasi, G., Malkani, R. G., Braun, R., Weintraub, S., Paller, K. A., & Zee, P. C. (2017). Acoustic enhancement of sleep slow oscillations and concomitant memory improvement in older adults. Frontiers in Human Neuroscience, 11. https://doi.org/10.3389/fnhum.2017.00109
Peek, C. B., Levine, D. C., Cedernaes, J., Taguchi, A., Kobayashi, Y., Tsai, S. J., Bonar, N. A., McNulty, M. R., Ramsey, K. M., & Bass, J. (2017). Circadian Clock Interaction with HIF1α Mediates Oxygenic Metabolism and Anaerobic Glycolysis in Skeletal Muscle. Cell Metabolism, 25(1), 86–92. https://doi.org/10.1016/j.cmet.2016.09.010
Peers, C., Dallas, M. L., Boycott, H. E., Scragg, J. L., Pearson, H. A., & Boyle, J. P. (2009). Hypoxia and neurodegeneration. Annals of the New York Academy of Sciences, 1177(1), 169– 177. https://doi.org/10.1111/j.1749-6632.2009.05026.x
Penzel, T., Kantelhardt, J., Grote, L., Peter, J., & Bunde, A. (2003). Comparison of detrended fluctuation analysis and spectral analysis for heart rate variability in sleep and sleep apnea. IEEE Transactions on Biomedical Engineering, 50(10), 1143–1151. https://doi.org/10.1109/tbme.2003.817636
Polak, J., Shimoda, L. A., Drager, L. F., Undem, C., McHugh, H., Polotsky, V. Y., & Punjabi, N. M. (2013). Intermittent Hypoxia Impairs Glucose Homeostasis in C57BL6/J Mice: Partial Improvement with Cessation of the Exposure. Sleep, 36(10), 1483–1490. https://doi.org/10.5665/sleep.3040
Puchowicz, M. A., Parveen, K., Sethuraman, A., Ishrat, T., Xu, K., & LaManna, J. (2023). Pro-survival phenotype of HIF-1Α: neuroprotection through inflammatory mechanisms. In Advances in Experimental Medicine and Biology (pp. 33–36). Springer International Publishing. https://doi.org/10.1007/978-3-031-42003-0_6
Punjabi, N. M. (2008). The Epidemiology of Adult Obstructive Sleep Apnea. Proceedings of the American Thoracic Society, 5(2), 136–143. https://doi.org/10.1513/pats.200709-155mg
Qiu, Y., Cheng, L., Xiong, Y., Liu, Z., Shen, C., Wang, L., Lu, Y., Wei, S., Zhang, L., Yang, S. B., & Zhang, X. (2025). Advances in the study of necroptosis in Vascular dementia: Focus on Blood–Brain barrier and neuroinflammation. CNS Neuroscience & Therapeutics, 31(2). https://doi.org/10.1111/cns.70224
Rábago-Monzón, Á. R., Armienta-Rojas, D. A., & De La Herrán- Arita, A. K. (2026). Developmental symbiosis in immunity: Microbiome–immune interactions from infancy to adulthood. Microbes & Immunity, 3(2), 025340084. https://doi.org/10.36922/mi025340084
Rábago-Monzón, Á. R., Osuna-Ramos, J. F., Armienta-Rojas, D. A., Camberos-Barraza, J., Camacho-Zamora, A., Magaña- Gómez, J. A., & De La Herrán-Arita, A. K. (2025). Stress- Induced Sleep Dysregulation: The roles of astrocytes and microglia in neurodegenerative and psychiatric disorders. Biomedicines, 13(5), 1121. https://doi.org/10.3390/biomedicines13051121
Rennels, M. L., Gregory, T. F., Blaumanis, O. R., Fujimoto, K., & Grady, P. A. (1985). Evidence for a ‘Paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Research, 326(1), 47–63. https://doi.org/10.1016/0006-8993(85)91383-6
Roy, B., Nunez, A., Aysola, R. S., Kang, D. W., Vacas, S., & Kumar, R. (2022). Impaired glymphatic system actions in obstructive sleep apnea adults. Frontiers in Neuroscience, 16. https://doi.org/10.3389/fnins.2022.884234
Semenza G. L. (2000). HIF-1 and human disease: one highly involved factor. Genes & Development, 14(16), 1983–1991.
Semenza, G. L. (2012). Hypoxia-Inducible Factors in Physiology and Medicine. Cell, 148(3), 399–408. https://doi.org/10.1016/j.cell.2012.01.021
Shen, J., Yang, Y., Chen, F., Zuo, Y., Yang, Y., Wei, W., Liu, Y., & Wen, J. (2025). Impaired glymphatic transport in hypoxic-ischemic encephalopathy. Neuroimage, 318, 121414. https://doi.org/10.1016/j.neuroimage.2025.121414
Shokri-Kojori, E., Wang, G., Wiers, C. E., Demiral, S. B., Guo, M., Kim, S. W., Lindgren, E., Ramirez, V., Zehra, A., Freeman, C., Miller, G., Manza, P., Srivastava, T., De Santi, S., Tomasi, D., Benveniste, H., & Volkow, N. D. (2018). β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proceedings of the National Academy of Sciences, 115(17), 4483–4488. https://doi.org/10.1073/pnas.1721694115
Simka, M., Latacz, P., & Czaja, J. (2018). Possible role of glymphatic system of the brain in the pathogenesis of High- Altitude Cerebral Edema. High Altitude Medicine & Biology, 19(4), 394–397. https://doi.org/10.1089/ham.2018.0066
Smolensky M. H. (1996). Chronobiology and chronotherapeutics. Applications to cardiovascular medicine. American Journal of Hypertension, 9(4), 11S–21S. https://doi.org/10.1016/0895-7061(95)00405-x
Somers, V. K., Dyken, M. E., Clary, M. P., & Abboud, F. M. (1995). Sympathetic neural mechanisms in obstructive sleep apnea. Journal of Clinical Investigation, 96(4), 1897–1904. https://doi.org/10.1172/jci118235
Spira, A. P., Gamaldo, A. A., An, Y., Wu, M. N., Simonsick, E. M., Bilgel, M., Zhou, Y., Wong, D. F., Ferrucci, L., & Resnick, S. M. (2013). Self-reported sleep and Β-Amyloid deposition in Community-Dwelling Older Adults. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2013.4258
Sprecher, K. E., Bendlin, B. B., Racine, A. M., Okonkwo, O. C., Christian, B. T., Koscik, R. L., Sager, M. A., Asthana, S., Johnson, S. C., & Benca, R. M. (2015). Amyloid burden is associated with self-reported sleep in nondemented late middle-aged adults. Neurobiology of Aging, 36(9), 2568– 2576. https://doi.org/10.1016/j.neurobiolaging.2015.05.004
Sun, X., He, G., Qing, H., Zhou, W., Dobie, F., Cai, F., Staufenbiel, M., Huang, L. E., & Song, W. (2006). Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proceedings of the National Academy of Sciences, 103(49), 18727–18732. https://doi.org/10.1073/pnas.0606298103
Sundman, M. H., Liu, Y., Chen, N., & Chou, Y. (2025). The glymphatic system as a therapeutic target: TMS-induced modulation in older adults. Frontiers in Aging Neuroscience, 17. https://doi.org/10.3389/fnagi.2025.1597311
Suresh, M. V., Balijepalli, S., Solanki, S., Aktay, S., Choudhary, K., Shah, Y. M., & Raghavendran, K. (2023). Hypoxia- Inducible Factor 1Α and its role in lung injury: adaptive or maladaptive. Inflammation, 46(2), 491–508. https://doi.org/10.1007/s10753-022-01769-z
Tan, L., Zhang, X., Fu, Z., Dong, C., Zhou, C., Hou, C., Lin, Y., Wang, X., Li, L., & Zhou, J. (2025). Effect of CPAP treatment on subjective cognitive decline in patients with mild obstructive sleep apnea syndrome. Sleep and Biological Rhythms, 24(1), 123–130. https://doi.org/10.1007/s41105-025-00620-w
Taoka, T., Masutani, Y., Kawai, H., Nakane, T., Matsuoka, K., Yasuno, F., Kishimoto, T., & Naganawa, S. (2017). Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer’s disease cases. Japanese Journal of Radiology, 35(4), 172–178. https://doi.org/10.1007/s11604-017-0617-z
Van Veluw, S. J., Hou, S. S., Calvo-Rodriguez, M., Arbel-Ornath, M., Snyder, A. C., Frosch, M. P., Greenberg, S. M., & Bacskai, B. J. (2019). Vasomotion as a driving force for paravascular clearance in the awake mouse brain. Neuron, 105(3), 549- 561.e5. https://doi.org/10.1016/j.neuron.2019.10.033
Verkman, A., Binder, D. K., Bloch, O., Auguste, K., & Papadopoulos, M. C. (2006). Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochimica Et Biophysica Acta (BBA) - Biomembranes, 1758(8), 1085–1093. https://doi.org/10.1016/j.bbamem.2006.02.018
Veschini, L., Belloni, D., Foglieni, C., Cangi, M. G., Ferrarini, M., Caligaris-Cappio, F., & Ferrero, E. (2006). Hypoxia-inducible transcription factor–1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib. Blood, 109(6), 2565–2570. https://doi.org/10.1182/blood-2006-06-032664
Villalobos-Valdez, G., Alemán-Villa, K. M., Armienta-Rojas, D. A., & De La Herrán-Arita, A. K. (2026). The sleep– microbiome–neurodegeneration triad: A new frontier in neuroimmunology. Microbes & Immunity, 0(0), 026020009. https://doi.org/10.36922/mi026020009
Villalobos-Valdez, G., Alemán-Villa, K. M., Armienta-Rojas, D. A., & De La Herrán-Arita, A. K. (2026b). The beat that clears the brain: Cardiac pulsatility as a driver of glymphatic flow during sleep. Brain & Heart, 0(0), 025390057. https://doi.org/10.36922/bh025390057
Wang, C., Wang, C., Yan, M., Jiang, H., Wang, Q., He, S., Chen, J., Wang, C., & Wang, C. (2017). Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin. Life Sciences, 193, 270–281. https://doi.org/10.1016/j.lfs.2017.10.021
Wilson, M. H., Newman, S., & Imray, C. H. (2009). The cerebral effects of ascent to high altitudes. The Lancet Neurology, 8(2), 175–191. https://doi.org/10.1016/s1474-4422(09)70014-6
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., Takano, T., Deane, R., & Nedergaard, M. (2013). Sleep Drives Metabolite Clearance from the Adult Brain. Science, 342(6156), 373–377. https://doi.org/10.1126/science.1241224
Xiong, A., Li, J., Xiong, R., Xia, Y., Jiang, X., Cao, F., Lu, H., Xu, J., & Shan, F. (2022). Inhibition of HIF-1α-AQP4 axis ameliorates brain edema and neurological functional deficits in a rat controlled cortical injury (CCI) model. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-06773-9
Yackle, K., Schwarz, L. A., Kam, K., Sorokin, J. M., Huguenard, J. R., Feldman, J. L., Luo, L., & Krasnow, M. A. (2017). Breathing control center neurons that promote arousal in mice. Science, 355(6332), 1411–1415. https://doi.org/10.1126/science.aai7984
Yang, C., Hawkins, K. E., Doré, S., & Candelario-Jalil, E. (2019). Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. American Journal of Physiology- Cell Physiology, 316(2), C135–C153. https://doi.org/10.1152/ajpcell.00136.2018
Yao, J., Huang, T., Tian, Y., Zhao, H., Li, R., Yin, X., Shang, S., & Chen, Y. (2024). Early detection of dopaminergic dysfunction and glymphatic system impairment in Parkinson’s disease. Parkinsonism & Related Disorders, 127, 107089. https://doi.org/10.1016/j.parkreldis.2024.107089
Zhang, P., Chen, J. S., Li, Q. Y., Sheng, L. X., Gao, Y. X., Lu, B. Z., Zhu, W. B., Zhan, X. Y., Li, Y., Yuan, Z. B., Xu, G., Qiu, B. T., Yan, M., Guo, C. X., Wang, Y. Q., Huang, Y. J., Zhang, J. X., Liu, F. Y., Tang, Z. W., Lin, S. Z., … Yan, G. M. (2020). Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys. Zoological Research, 41(1), 3–19. https://doi.org/10.24272/j.issn.2095-8137.2020.012
Zhang, S., Meng, F., Rong, Y., Zhang, Y., & Liu, H. (2025). Dexmedetomidine and the glymphatic system: a new perspective in managing postoperative cognitive dysfunction. Frontiers in Pharmacology, 16. https://doi.org/10.3389/fphar.2025.1648308
Zhang, W., Qi, D., Pei, X., Lu, D., Ba, M., Xuan, S., Huang, D., Yang, T., Yang, J., Li, Z., & Huang, S. (2025). Circadian disruption and ROS-NLRP3 signaling mediate sleep deprivation-enhanced silica nanoparticle toxicity in lacrimal glands. Journal of Nanobiotechnology, 23(1). https://doi.org/10.1186/s12951-025-03630-5
Zhang, X., Zhou, K., Wang, R., Cui, J., Lipton, S. A., Liao, F., Xu, H., & Zhang, Y. (2007). Hypoxia-inducible factor 1Α (HIF-1Α)-mediated hypoxia increases BACE1 expression and Β-Amyloid generation. Journal of Biological Chemistry, 282(15), 10873–10880. https://doi.org/10.1074/jbc.m608856200
Zhao, Y., Xiong, W., Li, C., Zhao, R., Lu, H., Song, S., Zhou, Y., Hu, Y., Shi, B., & Ge, J. (2023). Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets. Signal Transduction and Targeted Therapy, 8(1). https://doi.org/10.1038/s41392-023-01652-9
Zlokovic, B. V. (2011). Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature Reviews. Neuroscience, 12(12), 723–738. https://doi.org/10.1038/nrn3114
Zou, W., Pu, T., Feng, W., Lu, M., Zheng, Y., Du, R., Xiao, M., & Hu, G. (2019). Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein. Translational Neurodegeneration, 8(1). https://doi.org/10.1186/s40035-019-0147-y
