The central nervous system (CNS) is unique in being the only organ system lacking lymphatic vessels to assist in the removal of interstitial metabolic waste products. Recent work has led to the discovery of the glymphatic system, a glial-dependent perivascular network that subserves a pseudolymphatic function in the brain. Within the glymphatic pathway, cerebrospinal fluid (CSF) enters the brain via periarterial spaces, passes into the interstitium via perivascular astrocytic aquaporin-4, and then drives the perivenous drainage of interstitial fluid (ISF) and its solute. Here, we review the role of the glymphatic pathway in CNS physiology, the factors known to regulate glymphatic flow, and the pathologic processes in which a breakdown of glymphatic CSF-ISF exchange has been implicated in disease initiation and progression. Important areas of future research, including manipulation of glymphatic activity aiming to improve waste clearance and therapeutic agent delivery, are also discussed.


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Literature Cited

  1. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. 1.  2015. The glymphatic system: a beginner's guide. Neurochem. Res. 40:2583–99 [Google Scholar]
  2. Trevaskis NL, Kaminskas LM, Porter CJH. 2.  2015. From sewer to saviour—targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14:11781–803 [Google Scholar]
  3. Oliver G. 3.  2004. Lymphatic vasculature development. Nat. Rev. Immunol. 4:135–45 [Google Scholar]
  4. Cserr HF. 4.  1971. Physiology of the choroid plexus. Physiol. Rev. 51:2273–311 [Google Scholar]
  5. Hladky SB, Barrand MA. 5.  2014. Mechanisms of fluid movement into, through, and out of the brain: evaluation of the evidence. Fluids Barriers CNS 11:126 [Google Scholar]
  6. Keep R, Jones H. 6.  1990. A morphometric study on the development of the lateral ventricle choroid plexus, choroid plexus capillaries, and ventricular ependyma in the rat. Brain Res. Dev. Brain Res. 56:147–53 [Google Scholar]
  7. Maxwell D, Please D. 7.  1956. The electron microscopy of the choroid plexus. J. Biophys. Biochem. Cytol. 2:4467–74 [Google Scholar]
  8. Damkier HH, Brown PD, Praetorius J. 8.  2013. Cerebrospinal fluid secretion by the choroid plexus. Physiol. Rev. 93:41847–92 [Google Scholar]
  9. Brightman MW, Reese TS. 9.  1969. Junctions between intimately apposed cell membranes in the vertebrate brain. J. Cell Biol. 40:3648–77 [Google Scholar]
  10. Kratzer I, Vasiljevic A, Rey C, Fevre-Montange M, Saunder N. 10.  et al. 2012. Complexity and developmental changes in the expression pattern of claudins at the blood-CSF barrier. Histochem. Cell Biol. 138:6861–79 [Google Scholar]
  11. Hladky SB, Barrand MA. 11.  2016. Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles. Fluids Barriers CNS 13:19 [Google Scholar]
  12. Praetorius J, Nielsen S. 12.  2006. Distribution of sodium transporters and aquaporin-1 in the human choroid plexus. Am. J. Physiol. Cell Physiol. 291:1C59–67 [Google Scholar]
  13. Praetorius J. 13.  2007. Water and solute secretion by the choroid plexus. Pflugers Arch. Eur. J. Physiol. 454:11–18 [Google Scholar]
  14. Vates TJ, Bonting S, Oppelt W. 14.  1964. Na-K activated adenosine triphosphatase formation of cerebrospinal fluid in cat. Am. J. Physiol. 206:1165–72 [Google Scholar]
  15. Pollay M, Hisey B, Reynolds E, Tomkins P, Stevens F, Smith R. 15.  1985. Choroid plexus Na+/K+-activated adenosine triphosphatase and cerebrospinal fluid formation. Neurosurgery 17:5768–72 [Google Scholar]
  16. Papadopoulos MC, Verkman AS. 16.  2013. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci. 14:265–77 [Google Scholar]
  17. Johansson P, Dziegielewska K, Ek C, Habgood M, Møllgård K. 17.  et al. 2005. Aquaporin-1 in the choroid plexuses of developing mammalian brain. Cell Tissue Res 322:3353–64 [Google Scholar]
  18. Nielsen S, Smith B, Christensen E, Agre P. 18.  1993. Distribution of the aquaporin CHIP in secretory and resorptive epithelia and capillary endothelia. PNAS 90:157275–79 [Google Scholar]
  19. Oshio K, Song Y, Verkman A, Manley G. 19.  2003. Aquaporin-1 deletion reduces osmotic water permeability and cerebrospinal fluid production. Acta Neurochir. Suppl. 86:525–28 [Google Scholar]
  20. Oshio K, Watanabe H, Song Y, Verkman A, Manley G. 20.  2005. Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 19:176–78 [Google Scholar]
  21. Stokum JA, Gerzanich V, Simard JM. 21.  2016. Molecular pathophysiology of cerebral edema. J. Cereb. Blood Flow Metab. 36:3513–38 [Google Scholar]
  22. Farrell C, Yang J, Pardridge W. 22.  1992. GLUT-1 glucose transporter is present within apical and basolateral membranes of brain epithelial interfaces and in microvascular endothelia with and without tight junctions. J. Histochem. Cytochem. 40:2193–99 [Google Scholar]
  23. Fischbarg J, Kuang K, Hirsch J, Lecuona S, Rogozinski L. 23.  et al. 1989. Evidence that the glucose transporter serves as a water channel in J774 macrophages. PNAS 86:218397–401 [Google Scholar]
  24. Fischbarg J, Kuang K, Vera J, Arant S, Silverstein S. 24.  et al. 1990. Glucose transporters serve as water channels. PNAS 87:83244–47 [Google Scholar]
  25. Cserr HF, Ostrach LH. 25.  1974. Bulk flow of interstitial fluid after intracranial injection of Blue Dextran 2000. Exp. Neurol. 45:150–60 [Google Scholar]
  26. Cserr HF, Cooper DN, Milhorat TH. 26.  1977. Flow of cerebral interstitial fluid as indicated by the removal of extracellular markers from rat caudate nucleus. Exp. Eye Res. 25:Suppl.461–73 [Google Scholar]
  27. Szentistvanyi I, Patlak CS, Ellis RA, Cserr HF. 27.  1984. Drainage of interstitial fluid from different regions of rat brain. Am. J. Physiol. Ren. Physiol. 246:F835–44 [Google Scholar]
  28. Ball KK, Cruz NF, Mrak RE, Dienel GA. 28.  2010. Trafficking of glucose, lactate, and amyloid-β from the inferior colliculus through perivascular routes. J. Cereb. Blood Flow Metab. 30:1162–76 [Google Scholar]
  29. Thrane AS, Rangroo Thrane V, Nedergaard M. 29.  2014. Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci 37:620–28 [Google Scholar]
  30. Cserr HF, Cooper DN, Suri PK, Patlak CS. 30.  1981. Efflux of radiolabeled polyethylene glycols and albumin from rat brain. Am. J. Physiol. Ren. Physiol. 240:F319–28 [Google Scholar]
  31. Abbott NJ. 31.  2004. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem. Int. 45:4545–52 [Google Scholar]
  32. Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA. 32.  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 Res 326:47–63 [Google Scholar]
  33. Rennels ML, Blaumanis OR, Grady PA. 33.  1990. Rapid solute transport throughout the brain via paravascular fluid pathways. Adv. Neurol. 52:431–39 [Google Scholar]
  34. Blaumanis OR, Rennels ML, Grady PA. 34.  1990. Focal cerebral edema impedes convective fluid/tracer movement through paravascular pathways in cat brain. Adv. Neurol. 52:385–89 [Google Scholar]
  35. Ichimura T, Fraser PA, Cserr HF. 35.  1991. Distribution of extracellular tracers in perivascular spaces of the rat brain. Brain Res 545:1–2103–13 [Google Scholar]
  36. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W. 36.  et al. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4:147147ra111 [Google Scholar]
  37. Nagelhus EA, Ottersen OP. 37.  2013. Physiological roles of aquaporin-4 in brain. Physiol. Rev. 93:41543–62 [Google Scholar]
  38. Weed L. 38.  1914. Studies on cerebro-spinal fluid. No. III: the pathways of escape from the subarachnoid spaces with particular reference to the arachnoid villi. J. Med. Res. 31:151–91 [Google Scholar]
  39. Lee H, Xie L, Yu M, Kang H, Feng T. 39.  et al. 2015. The effect of body posture on brain glymphatic transport. J. Neurosci. 35:3111034–44 [Google Scholar]
  40. Iliff JJ, Lee H, Yu M, Feng T, Logan J. 40.  et al. 2013. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J. Clin. Investig. 123:31299–309 [Google Scholar]
  41. Bradbury MWB, Cole DF. 41.  1980. The role of the lymphatic system in drainage of cerebrospinal fluid and aqueous humour. J. Physiol. 299:353–65 [Google Scholar]
  42. Bradbury MW, Westrop RJ. 42.  1983. Factors influencing exit of substances from cerebrospinal fluid into deep cervical lymph of the rabbit. J. Physiol. 339:519–34 [Google Scholar]
  43. Bradbury MW, Cserr HF, Westrop RJ. 43.  1981. Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit. Am. J. Physiol. Ren. Physiol. 240:F329–36 [Google Scholar]
  44. Yamada S, DePasquale M, Patlak CS, Cserr HF. 44.  1991. Albumin outflow into deep cervical lymph from different regions of rabbit brain. Am. J. Physiol. Circ. Physiol. 261:H1197–204 [Google Scholar]
  45. Mathieu E, Gupta N, Macdonald RL, Ai J, Yucel YH. 45.  2013. In vivo imaging of lymphatic drainage of cerebrospinal fluid in mouse. Fluids Barriers CNS 10:35 [Google Scholar]
  46. Johnston M, Zakharov A, Papaiconomou C, Salmasi G, Armstrong D. 46.  2004. Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species. Cerebrospinal Fluid Res 1:12 [Google Scholar]
  47. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ. 47.  et al. 2015. Structural and functional features of central nervous system lymphatic vessels. Nature 523:7560337–41 [Google Scholar]
  48. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S. 48.  et al. 2015. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212:7991–99 [Google Scholar]
  49. Raper D, Louveau A, Kipnis J. 49.  2016. How do meningeal lymphatic vessels drain the CNS?. Trends Neurosci 39:9581–86 [Google Scholar]
  50. Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA. 50.  et al. 2013. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. 33:4618190–99 [Google Scholar]
  51. Kiviniemi V, Wang X, Korhonen V, Keinänen T, Tuovinen T. 51.  et al. 2015. Ultra-fast magnetic resonance encephalography of physiological brain activity—glymphatic pulsation mechanisms?. J. Cereb. Blood Flow Metab. 36:1033–45 [Google Scholar]
  52. Xie L, Kang H, Xu Q, Chen MJ, Liao Y. 52.  et al. 2013. Sleep drives metabolite clearance from the adult brain. Science 342:6156373–77 [Google Scholar]
  53. Lundgaard I, Lu ML, Yang E, Peng W, Mestre H. 53.  et al. 2017. Glymphatic clearance controls state-dependent changes in brain lactate concentration. J. Cereb. Blood Flow Metab. 37:2112–24 [Google Scholar]
  54. Lundgaard I, Li B, Xie L, Kang H, Sanggaard S. 54.  et al. 2015. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nat. Commun. 6:6807 [Google Scholar]
  55. Murlidharan G, Crowther A, Reardon RA, Song J, Asokan A. 55.  2016. Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain. JCI Insight 1:14e88034 [Google Scholar]
  56. Thrane VR, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ. 56.  et al. 2013. Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci. Rep. 3:2582 [Google Scholar]
  57. Maneshi MM, Maki B, Gnanasambandam R, Belin S, Popescu GK. 57.  et al. 2017. Mechanical stress activates NMDA receptors in the absence of agonists. Sci. Rep. 7:39610 [Google Scholar]
  58. Kress BT, Iliff JJ, Xia M, Wang M, Wei H. 58.  et al. 2014. Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76:845–61 [Google Scholar]
  59. Peng W, Achariyar TM, Li B, Liao Y, Mestre H. 59.  et al. 2016. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol. Dis. 93:215–25 [Google Scholar]
  60. Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz J-L. 60.  et al. 2014. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis?. Stroke 45:103092–96 [Google Scholar]
  61. Wang M, Ding F, Deng S, Guo X, Wang W. 61.  et al. 2017. Focal solute trapping and global glymphatic pathway impairment in a murine model of multiple microinfarcts. J. Neurosci. 37:2870–77 [Google Scholar]
  62. Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M. 62.  et al. 2014. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J. Neurosci. 34:4916180–93 [Google Scholar]
  63. Jiang Q, Zhang L, Ding G, Davoodi-Bojd E, Li Q. 63.  et al. 2017. Impairment of the glymphatic system after diabetes. J. Cereb. Blood Flow Metab. 37:1326–37 [Google Scholar]
  64. Brightman M. 64.  1992. Ultrastructure of brain endothelium. Physiology and Pharmacology of the Blood-Brain Barrier MWB Bradbury 1–22 Berlin/Heidelberg: Springer-Verlag [Google Scholar]
  65. Oldendorf W, Cornford M, Brown W. 65.  1977. The large apparent work capability of the blood-brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann. Neurol. 1:5409–17 [Google Scholar]
  66. Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare O. 66.  et al. 2011. Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood-brain water uptake and confers barrier function on perivascular astrocyte endfeet. PNAS 108:4317815–20 [Google Scholar]
  67. Cserr HF. 67.  1988. Role of secretion and bulk flow of brain interstitial fluid in brain volume regulation. Ann. N. Y. Acad. Sci. 529:19–20 [Google Scholar]
  68. Raichle ME, Hartman BK, Eichling JO, Sharpe LG. 68.  1975. Central noradrenergic regulation of cerebral blood flow and vascular permeability. PNAS 72:93726–30 [Google Scholar]
  69. Harik SI. 69.  1986. Blood-brain barrier sodium/potassium pump: modulation by central noradrenergic innervation. PNAS 83:114067–70 [Google Scholar]
  70. Raichle ME, Grubb RL. 70.  1978. Regulation of brain water permeability by centrally-released vasopressin. Brain Res 143:1191–94 [Google Scholar]
  71. Doczi T, Szerdahelyi P, Gulya K, Kiss J. 71.  1982. Brain water accumulation after the central administration of vasopressin. Neurosurgery 11:3402–7 [Google Scholar]
  72. Krieg SM, Sonanini S, Plesnila N, Trabold R. 72.  2015. Effect of small molecule vasopressin V1a and V2 receptor antagonists on brain edema formation and secondary brain damage following traumatic brain injury in mice. J. Neurotrauma 32:221–27 [Google Scholar]
  73. Zarow C, Lyness SA, Mortimer JA, Chui HC. 73.  2003. Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch. Neurol. 60:3337–41 [Google Scholar]
  74. Raskind MA, Peskind ER, Halter JB, Jimerson DC. 74.  1984. Norepinephrine and MHPG levels in CSF and plasma in Alzheimer's disease. Arch. Gen. Psychiatry 41:4343–46 [Google Scholar]
  75. Vulchanova L, Schuster DJ, Belur LR, Riedl MS, Podetz-Pedersen KM. 75.  et al. 2010. Differential adeno-associated virus mediated gene transfer to sensory neurons following intrathecal delivery by direct lumbar puncture. Mol. Pain 6:31 [Google Scholar]
  76. Yang L, Kress BT, Weber HJ, Thiyagarajan M, Wang B. 76.  et al. 2013. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11:107 [Google Scholar]
  77. Nedergaard M. 77.  2013. Garbage truck of the brain. Science 340:61401529–30 [Google Scholar]

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