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2008 Water movements in the brain

2008 Water movements in the brain

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Water movements in the brain:role of aquaporins
Matthew J. Tait, Samira Saadoun, B. Anthony Bell and Marios C. Papadopoulos
Academic Neurosurgery Unit, St. George’s University of London, Cranmer Terrace, Tooting, London SW17 0RE, UK
About 80% of the brain is water. This review discussestheimportanceofthethreebrainwater-channelproteins(AQP1, AQP4, AQP9) in brain physiology. AQP1 isexpressedinthechoroidplexusandparticipatesinform-ing cerebrospinal fluid. AQP4, found in astrocyte footprocesses, glia limitans and ependyma, facilitates watermovement into and out of the brain, accelerates astro-cyte migration and alters neuronal activity. Recently,AQP4 autoantibodies were discovered in patients withneuromyelitis optica, a demyelinating disease, and arenow being used to diagnose this condition. AQP9 ispresent in some glia and neurons, but its function isunclear. Finally, we discuss how the discovery of AQPactivators and inhibitors will be the next major step inthis field.Water channels: general properties
80% of the brain is water, relatively littleis known about brain water physiology. We now knowabout a family of water-channel proteins, called aquapor-ins (AQPs), which increase plasma membrane osmoticpermeability. The existence of AQPs was suspected long before their identification from experiments showing thatred blood cell membranes are more permeable to waterthan expected from water diffusion through a lipid bilayer[1]. In 1988, Peter Agre discovered the first water channel,termed AQP1[2], and was awarded the Nobel Prize inchemistry in 2003. He subsequently showed that frooocytes expressing AQP1 in their plasma membrane werefar more susceptible to osmotic lysis than nonexpressing oocytes[3], thus proving that AQP1 transports water. Todate, at least 13 AQPs have been found in mammals andmore than 300 in lower organisms.TheAQPsareproteinsthatassembleincellmembranesas tetramers[4,5]. Each monomer is
30 kDa and has sixmembrane-spanning domains surrounding a water porethat can transport water in both directions (Figure 1). AQPs selectively pass water, except for the aquaglycero-porins (AQP3, AQP7, AQP9), which also pass glycerol andsomepolar molecules.Mostofourknowledgeoftherolesof  AQPs in different tissues comes from experiments with AQP-null mice (reviewed in Ref.[4]). In general, AQPsincreasewaterpermeabilityacrossepithelia,thusallowing fast water flow to accompany active salt transport. Thisprinciple is illustrated by AQP5 deletion in mice, whichcauses the salivary and airway submucosal glands tosecrete a low volume of relatively hypertonic fluid[6,7]. AQPs also facilitate water flow in response to passiveosmotic gradients. For example, AQPs increase osmoticreabsorption of water from renal collecting ducts and, as aresult, AQP-deficient mice (AQPs 2–4) have impaired abil-ity to concentrate urine[8].Severalaquaglyceroporinfunctionshavebeendescribed,relatedtotheirglycerol-transportingability.Inhumansandrodents, AQP3 is found in skin keratinocytes. AQP3-nullmice have a dry, scaly skin because of reduced glycerolcontent in the stratum corneum and epidermis[9,10]. AQP7isexpressedinfatcells,andmicelackingAQP7carrmore fat than wild-type mice[11]. Because cell membraneglycerol permeability of AQP7-deficient fat cells is reduced,glycerol accumulates intracellularly and stimulates trigly-ceride synthesis.
AQP expression in brain
 AQP4, the principal AQP in mammalian brain, was firstcloned from rat lung [12]and was found in electrically excitable tissues including brain, spinal cord, retina, innerear and skeletal muscle[12–18]. A general paradigm isthat AQP4 is not expressed in excitable cells, but is foundinsupportingcells(astrocytesandependymainthecentralnervous system [CNS]; Mu¨ller glia in the retina; Hensen’s,Claudius and inner sulcus cells in the ear). Brain AQP4 isstrongly expressed at the borders between brain parench-ymaandmajorfluidcompartmentsincludingastrocytefootprocesses(brain–blood),glialimitans(brain–subarachnoidcerebrospinal fluid [CSF]), as well as ependymal cells and
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: Intracellular protein that may bind AQP4 and Kir4.1.
: Found in choroid plexus epithelium.
: Found in astrocyte foot processes, glia limitans, ependyma andsubependymal astrocytes.
: Found in some glia and neurons.
: Infiltrating astrocyte tumour, histologically graded I–IV.
Glia limitans externa
: Astrocyte processes bordering brain and subarachnoidCSF.
Glia limitans interna
: Astrocyte processes and ependyma bordering brain andventricular CSF.
: Inward rectifying K
channel that colocalizes with AQP4.
: A sheet-likecytoplasmic extension producedby migrating cells.
M1, M23
: AQP4 isoforms.
Neuromyelitis optica
: Autoimmune disease characterized by optic neuritis andmyelitis.
: Excess water accumulation in tissue (see Box 1).
Orthogonal array
: Square lattice arrangement of AQP4 tetramers in cellmembrane.
Corresponding author:
Papadopoulos, M.C. (mpapadop@sgul.ac.uk ). Available online 4 December 2007.
www.sciencedirect.com 0166-2236/$ – see front matter
2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2007.11.003
subependymal astrocytes (brain–ventricular CSF)[14,15].This pattern of distribution suggests that AQP4 controlswater flow into and out of the brain. Although AQP4 expression is polarized in astrocyte footprocesses adjacent to endothelial cells, in the absence of endothelia (e.g. cultured astrocytes[19], malignant astro-cytes[20,21], glial limitans and circumventricular organs[14,15]), AQP4 redistributes throughout the astrocyte cellmembrane.Thissuggeststhatendothelialcellssignalastro-cytes to polarize AQP4 expression in the cell membrane.Two AQP4 splice variants have been cloned from brain,M1andM23,whichformsquarearraysoftetramerswithinthe cell membrane[22,23]. According to a recent study, therelativeamountsofM1versusM23isoformsdeterminethesize of these arrays, which can contain up to hundreds of tetramers[23].ItisnotknownwhyAQP4formsorthogonalarrays. We propose that orthogonally interconnected tet-ramers allow more efficient anchoring of AQP4 to intra-cellularproteins,suchas
-syntrophin[24],comparedwithnoninteracting AQP4 tetramers. For example, to restrict AQP4 expression to astrocyte endfeet, each noninteracting  AQP4 tetramer would need its own intracellular anchor,compared with one anchor per array.There are several, often inconsistent, reports of altered AQP4 expression in different diseases. Such inconsisten-cies probably arise because of different AQP detectionmethods (mRNA versus protein), antibody specificities,tissue processing, species-specific responses and insultseverities. In general, AQP4 expression is upregulatedin astrocytes associated with brain oedema. For example, AQP4 overexpression in human astrocytomas correlateswith the presence of brain oedema on magnetic resonancescans[20,21]. Correlations between AQP4 expression andbrain oedema have been reported after brain ischaemia[25,26]and traumatic brain injury [25,27]in rodents. Such studies reinforce the notion that AQP4 plays an importantrole in the formation and/or absorption of brain oedemafluid. AQP4 expression also becomes upregulated in reac-tive astrocytes and reactive microglia[19,28], suggesting apossible role in glial scar formation. Overall, regulationstudies provide only indirect evidence about the functionsof AQP4 in the brain. A recent intriguing discovery is the detection of AQP4autoantibodies in the sera of human patients with neuro-myelitis optica (NMO; Devic’s syndrome), a demyelinating condition[29].NMOserumimmunostainedmousebrainina pattern corresponding to AQP4 distribution, with noimmunoreactivity in AQP4-null mice. NMO serum alsoimmunostained AQP4-expressing, but not AQP4-lacking,cultured cells. This exciting finding has led to the devel-opment of an objective diagnostic test for NMO. Somepublications have suggested that AQP4 autoantibodiescauseNMO, probablybyinhibiting AQP4[30,31]. Toprovecausality, however, it is essential to show that adminis-tering the autoantibody (e.g. to mice) causes NMO, whichhas not been demonstrated. The idea that AQP4 autoanti-bodiescauseNMOraisesseveralquestions(Box1).Despitereservations, the discovery of AQP4 autoantibodies inNMO is an interesting observation and suggests thatautoantibodies against other AQPs may also play a rolein other diseases.
 AQP1 is expressed in the apical membrane of the choroidplexus, and plays a role in forming CSF[32]. AQP1 isupregulated in choroid plexus tumours[33], which are
Box 1. Does AQP4 autoantibody cause NMO? Outstandingquestions
AlthoughAQP4isexpressedinkidneys,lung,inner ear,muscleandintestine, these organs are unaffected in NMO, even though theyare more accessible to AQP4 autoantibodies than the CNS. Even if weassumethat AQP4 function isunimportant intheseorgans,whydoes AQP4 autoantibody binding and downstream destructiveevents (such as complement activation) not damage these tissues?
Although AQP4 is ubiquitously expressed throughout the CNS,why does NMO primarily cause optic and spinal cord lesions?
Peripherally formed AQP4 autoantibodies cannot enter brain. Isthere a preceding event that opens the BBB?
Is AQP4 channel inhibition by AQP4 autoantibody necessary forNMO to develop? AQP4 deletion does not cause NMO-likephenotype in mice.
Does serum from patients with NMO cause NMO-type diseasewhen given to wild-type, but not to AQP4-null, mice?
Figure 1
. Schematic showing AQP1 structure.
AQP1 monomer consists of six
-helical domains (H1–H6) around a water pore, two conserved NPA motifs (Asn-Pro-Ala)that allow water but not small solutes to pass across the pore, and intracellular N and C termini.
Tetrameric arrangement of AQP1 in membrane. Each monomer has awater pore.
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associatedwithincreasedCSFproduction,againsupporting aroleforAQP1inCSFsecretion.Interestingly,AQP1isnotfound in normal brain capillary endothelium, althoughhighly expressed in peripheral endothelial cells[34,35].Cerebral capillary endothelial cells cultured in the absenceofastrocytes[34]andcapillaryendothelialcellswithinbraintumours (which are not surrounded by astrocyte endfeet)express AQP1[36]. These observations suggest that astro-cyte endfeet may signal adjacent endothelial cells to switchoff endothelial AQP1 expression, although the precise sig-nalling remains unknown. AQP1 is also found in small-diameter sensory neurons in dorsal root, trigeminal andnodose ganglia, but studies of a possible role for AQP1 inpain sensation have yielded conflicting results[37,38].
 AQP9 immunoreactivity in rat brain has been observed insome white-matter astrocytes, Bergmann glia and a sub-population of glia called tanycytes (reviewed in Ref.[39]).Because AQP9 transports energy substrates (glycerol, lac-tate), AQP9 may play a role in controlling cerebral energy metabolism. Further support for this idea comes fromreports of AQP9 immunoreactivity in glucose-sensitivecatecholaminergic neurons[39]and in mitochondria[40]. In general, AQP9 protein expression becomes upregulatedin several brain diseases (reviewed in Ref.[39]), forexample in astrocytes bordering cerebral infarcts in mice.It has been suggested that AQP9 facilitates the clearanceof lactate during reperfusion. We urge caution, however,when interpreting AQP9 protein expression studies. ThecomparableAQP9immunoreactivitiesseeninthebrainsof wild-type and AQP9-null mice[41]suggest that AQP9antibodies might crossreact with other proteins.
AQP functions in brain
Experiments comparing wild-type versus AQP4-null mice(or
-syntrophin-null mice, which have disrupted AQP4expression) revealed three major roles for AQP4 in brain: AQP4 controls water movements into and out of the brain,facilitatesastrocyte migration and alters neuronal activity. AQP1 plays a role in forming CSF. Because of the lack of  AQP9-null mice until recently, the functions of AQP9 inbrain are less well characterized.
Water movements into and out of brain 
The normal adult human intracranial cavity (
1.4 L) com-prises several compartments including blood (
100 mL),CSF (
100 mL) and brain parenchyma intracellular(
1.1 L) and interstitial (
100 mL) spaces. Water flowsbetween these compartments in response to osmotic andhydrostatic forces. In several diseases, the brain swellsbecause excess water accumulates in the brain parench-yma. To understand the role of AQP4 in brain swelling, weneed toconsider themain types of brainoedema, cytotoxic, vasogenic and hydrocephalic, defined inBox 2.There is mounting evidence that AQP4 deficiency isassociated with reduced cytotoxic brain oedema in mousemodels, including water intoxication, focal cerebral ischae-mia[42]andbacterialmeningitis[43].Forexample,AQP4- null mice develop 35% less hemispheric brain swelling than wild-type mice 24 h after middle cerebral artery occlusion[42]. Reduced brain swelling after cerebralischaemia and water intoxication has also been reportedin
-syntrophin-null mice, which have reduced AQP4expression in astrocyte foot processes[44,45]. Comparedwith wild-type mice, in AQP4-[43]and
-syntrophin-[44]deficient mice the rate of water uptake into brain parench-yma after water intoxication is reduced ninefold[43].Water molecules moving from the blood, through intactblood–brain barrier (BBB), into brain cross three cellmembranes: luminal and basal endothelial membranesthat lack AQPs, and astrocyte foot process membrane thatcontains AQP4. Water moves across the endothelium by simple diffusion and vesicular transport, and across theastrocyte foot process primarily through AQP4 channels.These membranes are equivalent to three resistors inseries, with the astrocyte membrane resistance substan-tially increased in AQP4 deficiency. The routes for waterentry into brain are shown inFigure 2.In contrast to its beneficial role in cytotoxic oedema, AQP4 deficiency produces more brain swelling in mousemodels of vasogenic oedema, including brain tumour, infu-sion of normal saline into brain extracellular space (ECS)and focal cortical freeze injury (that renders the BBBleaky)[46]. Melanoma cells implanted in brains of wild-type and AQP4-null mice produce comparable tumours(
45 mm
)afteraweekwithhigherintracranialpressuresin AQP4-null mice (40 versus 20 cmH
O). These findings
Box 2. Brain oedema
The main types of brain oedema are (i) cytotoxic, (ii) vasogenic and(iii) hydrocephalic, with each involving different routes of waterentry into brain[69].(i) Cytotoxic oedemaiscellswelling,associatedwitha reducedECSvolumeand intactBBB.Waterflowsfrom thevasculatureintotheintracellular brain compartment when the Na
ATPase fails orextracellular [Na
] falls. Cytotoxic oedema is produced by early-phase cerebral ischaemia, hypoxia and hyponatraemia.(ii) In vasogenic oedema, hydrostatic forces cause extravasation of a protein-rich exudate from plasma, through leaky BBB intobrain ECS, causing ECS expansion. Brain tumour and brainabscess produce vasogenic oedema.(iii) Hydrocephalic oedema arises when CSF pressure is high,causing CSF extravasation through ependyma into periventri-cular brain. The excess fluid is evident on computed tomogramand magnetic resonance scans as ‘periventricular lucencies.’As the brain swells inside the noncompliant skull, intracranialpressure rises, causing brain ischaemia, herniation and eventuallydeath.
Figure 2
. Routes of water flow into the brain.
In cytotoxic oedema, water movesfrom the blood through endothelial cells and astrocyte foot process membrane(through AQP4) into brain.
In vasogenic oedema, water moves from blooddown a hydrostatic pressure gradient through a leaky BBB into brain ECS. Waterentry is not through AQP4.
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