glymphatic system

File:Astrocytes.jpg

In a study published in 2012,{{cite journal | vauthors = Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M | display-authors = 6 | title = A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β | journal = Science Translational Medicine | volume = 4 | issue = 147 | pages = 147ra111 | date = August 2012 | pmid = 22896675 | pmc = 3551275 | doi = 10.1126/scitranslmed.3003748 }} a group of researchers from the University of Rochester, headed by Maiken Nedergaard, used in-vivo two-photon imaging of small fluorescent tracers to monitor the flow of subarachnoid CSF into and through the brain parenchyma. The two-photon microscopy allowed the Rochester team to visualize the flux of CSF in living mice, in real time, without needing to puncture the CSF compartment (imaging was performed through a closed cranial window). According to findings of that study, subarachnoid CSF enters the brain rapidly, along the paravascular spaces surrounding the penetrating arteries, then exchanges with the surrounding interstitial fluid. Similarly, interstitial fluid is cleared from the brain parenchyma via the paravascular spaces surrounding large draining veins.

Paravascular spaces are CSF-filled channels formed between the brain blood vessels and leptomeningeal sheathes that surround cerebral surface vessels and proximal penetrating vessels. Around these penetrating vessels, paravascular spaces take the form of Virchow-Robin spaces. Where the Virchow-Robin spaces terminate within the brain parenchyma, paravascular CSF can continue traveling along the basement membranes surrounding arterial vascular smooth muscle, to reach the basal lamina surrounding brain capillaries. CSF movement along these paravascular pathways is rapid and arterial pulsation has long been suspected as an important driving force for paravascular fluid movement. In a study published in 2013, J. Iliff and colleagues demonstrated this directly, using in vivo two-photon microscopy. The authors reported that when cerebral arterial pulsation was either increased or decreased, the rate of paravascular CSF flux in turn increased or decreased, respectively.{{citation needed|date= November 2021}}

Astrocytes extend long processes that interface with neuronal synapses, as well as projections referred to as 'end-feet' that completely ensheathe the brain's entire vasculature. Astrocytes are known to facilitate changes in blood flow {{cite journal | vauthors = Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M | title = Astrocyte-mediated control of cerebral blood flow | journal = Nature Neuroscience | volume = 9 | issue = 2 | pages = 260–7 | date = February 2006 | pmid = 16388306 | doi = 10.1038/nn1623 | s2cid = 6140428 }}{{cite journal | vauthors = Schummers J, Yu H, Sur M | title = Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex | journal = Science | volume = 320 | issue = 5883 | pages = 1638–43 | date = June 2008 | pmid = 18566287 | doi = 10.1126/science.1156120 | bibcode = 2008Sci...320.1638S | s2cid = 16895889 }} and have long been thought to play a role in waste removal in the brain.{{cite journal|vauthors =Yuhas D |title=How the brain cleans itself|journal=Nature|year=2012|issn=1476-4687|doi=10.1038/nature.2012.11216 |s2cid=183462941}} Astrocytes express water channels called aquaporins.{{cite journal | vauthors = Amiry-Moghaddam M, Ottersen OP | title = The molecular basis of water transport in the brain | journal = Nature Reviews. Neuroscience | volume = 4 | issue = 12 | pages = 991–1001 | date = December 2003 | pmid = 14682361 | doi = 10.1038/nrn1252 | s2cid = 23975497 }} Until 2000, no physiological function had been identified that explained their presence in the mammalian CNS. Aquaporins are membrane-bound channels and regulate the flux of water into and out of cells. Relative to simple diffusion, they increases water permeability 3– to 10-fold.{{cite journal | vauthors = Verkman AS, Mitra AK | title = Structure and function of aquaporin water channels | journal = American Journal of Physiology. Renal Physiology | volume = 278 | issue = 1 | pages = F13-28 | date = January 2000 | pmid = 10644652 | doi = 10.1152/ajprenal.2000.278.1.F13 }}

The two types of aquaporins expressed in the CNS are aquaporin-1, which is expressed by specialized epithelial cells of the choroid plexus, and aquaporin-4 (AQP4), which is expressed by astrocytes.{{cite journal | vauthors = Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC | title = Three distinct roles of aquaporin-4 in brain function revealed by knockout mice | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1758 | issue = 8 | pages = 1085–93 | date = August 2006 | pmid = 16564496 | doi = 10.1016/j.bbamem.2006.02.018 | doi-access = free }}{{cite journal | vauthors = Yool AJ | title = Aquaporins: multiple roles in the central nervous system | journal = The Neuroscientist | volume = 13 | issue = 5 | pages = 470–85 | date = October 2007 | pmid = 17901256 | doi = 10.1177/1073858407303081 | s2cid = 46231509 }} Aquaporin-4 expression in astrocytes is highly polarized to the endfoot processes ensheathing the cerebral vasculature. Up to 50% of the vessel-facing endfoot surface that faces the vasculature is occupied by orthogonal arrays of AQP4.

In 2012, it was shown that AQP4 is essential for paravascular CSF–ISF exchange. Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow-dependent clearance of interstitial solutes decreases by 70% in the absence of AQP4. Based upon this role of AQP4-dependent glial water transport in the process of paravascular interstitial solute clearance, Iliff and Nedergaard termed this brain-wide glio-vascular pathway the "glymphatic system".

A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Using a combination of diffusion iontophoresis techniques pioneered by Nicholson and colleagues, in vivo 2-photon imaging, and electroencephalography to confirm the wake and sleep states, Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta. On the basis of these findings, they hypothesized that the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain.{{cite journal | vauthors = Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M | display-authors = 6 | title = Sleep drives metabolite clearance from the adult brain | journal = Science | volume = 342 | issue = 6156 | pages = 373–7 | date = October 2013 | pmid = 24136970 | pmc = 3880190 | doi = 10.1126/science.1241224 | bibcode = 2013Sci...342..373X }} The flow is elicited by slow variations in the release of noradrenaline by the locus coeruleus.{{Cite journal |last=Hauglund |first=Natalie L. |last2=Andersen |first2=Mie |last3=Tokarska |first3=Klaudia |last4=Radovanovic |first4=Tessa |last5=Kjaerby |first5=Celia |last6=Sørensen |first6=Frederikke L. |last7=Bojarowska |first7=Zuzanna |last8=Untiet |first8=Verena |last9=Ballestero |first9=Sheyla B. |last10=Kolmos |first10=Mie G. |last11=Weikop |first11=Pia |last12=Hirase |first12=Hajime |last13=Nedergaard |first13=Maiken |date=2025-02-06 |title=Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep |url=https://www.cell.com/cell/abstract/S0092-8674(24)01343-6 |journal=Cell |language=English |volume=188 |issue=3 |pages=606–622.e17 |doi=10.1016/j.cell.2024.11.027 |issn=0092-8674 |pmid=39788123|url-access=subscription |doi-access=free }}

Another key function of the glymphatic system was documented by Thrane et al., who, in 2013, demonstrated that the brain's system of paravascular pathways plays an important role in transporting small lipophilic molecules.{{cite journal | vauthors = Rangroo Thrane V, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ, Deane R, Nagelhus EA, Nedergaard M | display-authors = 6 | title = Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain | journal = Scientific Reports | volume = 3 | pages = 2582 | date = 2013 | pmid = 24002448 | pmc = 3761080 | doi = 10.1038/srep02582 | bibcode = 2013NatSR...3.2582T }}

Led by M. Nedergaard, Thrane and colleagues also showed{{when|date=January 2025}} that the paravascular transport of lipids through the glymphatic pathway activated glial calcium signalling and that the depressurization of the cranial cavity, and thus impairment of the glymphatic circulation, led to unselective lipid diffusion, intracellular lipid accumulation, and pathological signalling among astrocytes.{{citation needed|date=January 2025}}

Although further experiments are needed to parse out the physiological significance of the connection between the glymphatic circulation, calcium signalling, and paravascular lipid transport in the brain, the findings point to the adoption of a function in the CNS similar to the capacity of the intestinal lymph vessels (lacteals) to carry lipids to the liver.{{citation needed|date=January 2025}}

Pathologically, neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease are all characterized by the progressive loss of neurons, cognitive decline, motor impairments, and sensory loss.{{cite journal | vauthors = Mehler MF, Gokhan S | title = Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat | journal = Trends in Neurosciences | volume = 23 | issue = 12 | pages = 599–605 | date = December 2000 | pmid = 11137149 | doi = 10.1016/s0166-2236(00)01705-7 | s2cid = 21302044 }}{{cite journal | vauthors = Narasimhan K | title = Quantifying motor neuron loss in ALS | journal = Nature Neuroscience | volume = 9 | issue = 3 | pages = 304 | date = March 2006 | pmid = 16498424 | doi = 10.1038/nn0306-304 | s2cid = 1933099 | doi-access = free }} Collectively these diseases fall within a broad category referred to as proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins. According to the prevailing amyloid hypothesis of Alzheimer's disease, the aggregation of amyloid-beta (a peptide normally produced in and cleared from the healthy young brain) into extracellular plaques drives the neuronal loss and brain atrophy that is the hallmark of Alzheimer's dementia. Although the full extent of the involvement of the glymphatic system in Alzheimer's disease and other neurodegenerative disorders remains unclear, researchers have demonstrated through experiments with genetically modified mice that the proper function of the glymphatic clearance system was necessary to remove soluble amyloid-beta from the brain interstitium. In mice that lack the AQP4 gene, amyloid-beta clearance is reduced by approximately 55 percent.

The glymphatic system also may be impaired after acute brain injuries such as ischemic stroke, intracranial hemorrhage, or subarachnoid hemorrhage. In 2014, a group of researchers from the French Institute of Health and Medical Research (INSERM) demonstrated by MRI that the glymphatic system was impaired after subarachnoid hemorrhage, because of the presence of coagulated blood in the paravascular spaces.{{cite journal | vauthors = Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, Touze E, Vivien D, Gauberti M | display-authors = 6 | title = Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? | journal = Stroke | volume = 45 | issue = 10 | pages = 3092–6 | date = October 2014 | pmid = 25190438 | doi = 10.1161/STROKEAHA.114.006617 | doi-access = free }} Injection of tissue plasminogen activator (a fibrinolytic drug) in the CSF improved glymphatic functioning. In a parallel study, they also demonstrated that the glymphatic system was impaired after ischemic stroke in the ischemic hemisphere, although the pathophysiological basis of this phenomenon remains unclear. Notably, recanalization of the occluded artery also reestablished the glymphatic flow.

The glymphatic system may also be involved in the pathogenesis of amyotrophic lateral sclerosis.{{cite journal | vauthors = Ng Kee Kwong KC, Mehta AR, Nedergaard M, Chandran S | title = Defining novel functions for cerebrospinal fluid in ALS pathophysiology | journal = Acta Neuropathologica Communications | volume = 8 | issue = 1 | pages = 140 | date = August 2020 | pmid = 32819425 | doi = 10.1186/s40478-020-01018-0 | pmc = 7439665 | department = Review | doi-access = free }}

Although the first known observations of the CSF date back to Hippocrates (460–375 BCE) and later, to Galen (130–200 CE), its discovery is credited to Emanuel Swedenborg (1688–1772 CE), who, being a devoutly religious man, identified the CSF during his search for the seat of the soul.{{cite journal|last=Hajdu|first=Steven | name-list-style = vanc |journal=Annals of Clinical and Laboratory Science|year=2003|volume=33|issue=3|title=A Note from History: Discovery of the Cerebrospinal Fluid|url=http://www.annclinlabsci.org/content/33/3/334.full.pdf}} The 16 centuries of anatomists who came after Hippocrates and Galen may have missed identifying the CSF due to the prevailing autopsy technique of the time, which included severing the head and draining the blood before dissecting the brain. Although Swedenborg's work (in translation) was not published until 1887 due to his lack of medical credentials, he also may have made the first connection between the CSF and the lymphatic system. His description of the CSF was of a "spirituous lymph".

In 2015, the presence of a meningeal lymphatic system was first identified. Downstream of the glymphatic system's waste clearance from the ISF to the CSF, the meningeal lymphatic system drains fluid from the glymphatic system to the meningeal compartment and deep cervical lymph nodes; this is shown by the draining of fluorescent dyes injected intracisternally into the CSF in mice. The meningeal lymphatics also carry immune cells. The extent to which these cells may interact directly with the brain or glymphatic system, is unknown.{{citation needed|date=November 2021}}

For more than a century the prevailing hypothesis was that the flow of cerebrospinal fluid (CSF), which surrounds, but does not come in direct contact with the parenchyma of the CNS, could replace peripheral lymphatic functions and play an important role in the clearance of extracellular solutes.{{cite journal | vauthors = Abbott NJ, Pizzo ME, Preston JE, Janigro D, Thorne RG | title = The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system? | journal = Acta Neuropathologica | volume = 135 | issue = 3 | pages = 387–407 | date = March 2018 | pmid = 29428972 | doi = 10.1007/s00401-018-1812-4 | doi-access = free }}

The majority of the CSF is formed in the choroid plexus and flows through the brain along a distinct pathway: moving through the cerebral ventricular system, into the subarachnoid space surrounding the brain, then draining into the systemic blood column via arachnoid granulations of the dural sinuses or to peripheral lymphatics along cranial nerve sheathes.{{cite journal | vauthors = Abbott NJ | title = Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology | journal = Neurochemistry International | volume = 45 | issue = 4 | pages = 545–52 | date = September 2004 | pmid = 15186921 | doi = 10.1016/j.neuint.2003.11.006 | s2cid = 10441695 }}{{cite journal | vauthors = Bradbury MW, Cserr HF, Westrop RJ | title = Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit | journal = The American Journal of Physiology | volume = 240 | issue = 4 | pages = F329-36 | date = April 1981 | pmid = 7223890 | doi = 10.1152/ajprenal.1981.240.4.F329 }} Many researchers suggested that the CSF compartment constitutes a sink for interstitial solute and fluid clearance from the brain parenchyma.{{Citation needed|date=February 2017}} However, the distances between the interstitial fluid and the CSF in the ventricles and subarachnoid space are too great for the efficient removal of interstitial macromolecules and wastes by simple diffusion alone.{{Citation needed|date=February 2017}} In 1971, Helen Cserr at Brown University calculated that mean diffusion times for large molecules, such as albumin, would exceed 100 hours to traverse 1 cm of brain tissue,{{cite journal | vauthors = Cserr HF | title = Physiology of the choroid plexus | journal = Physiological Reviews | volume = 51 | issue = 2 | pages = 273–311 | date = April 1971 | pmid = 4930496 | doi = 10.1152/physrev.1971.51.2.273 }} a rate that is not compatible with the intense metabolic demands of brain tissue. Additionally, a clearance system based on simple diffusion would lack the sensitivity to respond rapidly to deviations from homeostatic conditions.{{citation needed|date=November 2021}} As an alternative explanation to diffusion, Cserr and colleagues proposed that convective bulk flow of interstitial fluid from the brain parenchyma to the CSF was responsible for efficient waste clearance.

Key determinants of diffusion through the brain interstitial spaces are the dimensions and composition of the extracellular compartment. In a series of elegantly designed experiments in the 1980s and 1990s, researchers from New York University explored the microenvironment of the extracellular space using ion-selective micropipettes and ionophoretic point sources. They showed that solute and water movement through the brain parenchyma slows as the extracellular volume fraction decreases and becomes more tortuous.{{cite journal | vauthors = Nicholson C, Phillips JM | title = Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum | journal = The Journal of Physiology | volume = 321 | pages = 225–57 | date = December 1981 | pmid = 7338810 | pmc = 1249623 | doi = 10.1113/jphysiol.1981.sp013981 }}

The continuity between the brain interstitial fluid and CSF was confirmed in 1981 by evidence that interstitial solutes in the brain exchange with CSF via a bulk flow mechanism, rather than by diffusion.

Studies in 1985 indicated that cerebrospinal fluid and interstitial fluid may flow along specific anatomical pathways within the brain, with CSF moving into the brain along the outside of blood vessels; such 'paravascular channels' were possibly analogous to peripheral lymph vessels, facilitating the clearance of interstitial wastes from the brain.{{cite journal | vauthors = Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA | title = 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 | journal = Brain Research | volume = 326 | issue = 1 | pages = 47–63 | date = February 1985 | pmid = 3971148 | doi = 10.1016/0006-8993(85)91383-6 | s2cid = 23583877 }}{{cite journal | vauthors = Rennels ML, Blaumanis OR, Grady PA | title = Rapid solute transport throughout the brain via paravascular fluid pathways | journal = Advances in Neurology | volume = 52 | pages = 431–9 | year = 1990 | pmid = 2396537 }} However, other studies did not observe such widespread paravascular CSF–ISF exchange.{{cite journal | vauthors = Pullen RG, DePasquale M, Cserr HF | title = Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality | journal = The American Journal of Physiology | volume = 253 | issue = 3 Pt 2 | pages = F538-45 | date = September 1987 | pmid = 3115117 | doi = 10.1152/ajprenal.1987.253.3.F538 }}{{cite journal | vauthors = Cserr HF, Cooper DN, Suri PK, Patlak CS | title = Efflux of radiolabeled polyethylene glycols and albumin from rat brain | journal = The American Journal of Physiology | volume = 240 | issue = 4 | pages = F319-28 | date = April 1981 | pmid = 7223889 | doi = 10.1152/ajprenal.1981.240.4.F319 }}

Glymphatic flow was initially believed to be the complete answer to the long-standing question of how the sensitive neural tissue of the CNS functions in the perceived absence of a lymphatic drainage pathway for extracellular proteins, excess fluid, and metabolic waste products. In 2015, two subsequent articles by Louveau et al. from the University of Virginia School of Medicine{{cite journal | vauthors = Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J | display-authors = 6 | title = Structural and functional features of central nervous system lymphatic vessels | journal = Nature | volume = 523 | issue = 7560 | pages = 337–41 | date = July 2015 | pmid = 26030524 | pmc = 4506234 | doi = 10.1038/nature14432 | bibcode = 2015Natur.523..337L }} and Aspelund et al. from the University of Helsinki reported independently that the dural sinuses and meningeal arteries are lined with conventional lymphatic vessels, and that this long-elusive vasculature forms a connecting pathway to the glymphatic system.{{cite journal | vauthors = Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K | display-authors = 6 | title = A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules | journal = The Journal of Experimental Medicine | volume = 212 | issue = 7 | pages = 991–9 | date = June 2015 | pmid = 26077718 | pmc = 4493418 | doi = 10.1084/jem.20142290 }}

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• {{cite journal | vauthors = Jessen NA, Munk AS, Lundgaard I, Nedergaard M | title = The Glymphatic System: A Beginner's Guide | journal = Neurochemical Research | volume = 40 | issue = 12 | pages = 2583–99 | date = December 2015 | pmid = 25947369 | pmc = 4636982 | doi = 10.1007/s11064-015-1581-6 }}

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Category:Lymphatic system

Category:Central nervous system

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