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Aquaporin 4

Aquaporin 4 also known as AQP4 is a protein which in humans is encoded by the AQP4 gene.

AQP4 belongs to the aquaporin family of integral membrane proteins that conduct water through the cell membrane.

Aquaporin-4 (AQP4) channels are transmembrane proteins that facilitate water transport in the brain. AQP4 channels are present throughout the brain, specifically concentrated in the end-feet of astrocytes and in the glia limitans interna and externa.

The highly polarized AQP4 expression indicates that these cells are equipped with specific membrane domains that are specialized for water transport, thereby mediating the flow of water between glial cells and the cavities filled with CSF and the intravascular space 1).

Multiple studies of transgenic mice with a complete deficiency or altered expression of AQP4 suggest a prominent role for AQP4 in cerebral water transport. In models of cellular (cytotoxic) edema, AQP4 deletion or alteration has been shown to be protective, reducing edema burden and improving overall survival. In contrast, AQP4 deletion in extracellular (vasogenic) edema results in decreased edema clearance and greater progression of disease. The data strongly support the conclusion that AQP4 plays a pivotal role in cerebral water transport and is an essential mediator in the formation and resorption of edema fluid from the brain parenchyma. These findings also suggest that drug therapy targeting AQP4 function and expression may dramatically alter our ability to treat cerebral edema 2).

Aquaporin-4 channels play a beneficial role in brain water clearance in vasogenic edema, but a detrimental role in cytotoxic edema and exacerbate cell swelling. In light of current evidence, we still do not have a complete understanding of the role of aquaporin-4 in brain water transport. In this review, we propose that the regulatory mechanisms of aquaporin-4 at the transcriptional, translational, and post-translational levels jointly regulate water permeability in the short and long time scale after injury. Furthermore, in order to understand why aquaporin-4 channels play opposing roles in cytotoxic and vasogenic edema, we discuss experimental evidence on the dynamically changing osmotic gradients between blood, extracellular space, and the cytosol during the formation of cytotoxic and vasogenic edema. We conclude with an emerging picture of the distinct osmotic environments in cytotoxic and vasogenic edema, and propose that the directions of aquaporin-4-mediated water clearance in these two types of edema are distinct. The difference in water clearance pathways may provide an explanation for the conflicting observations of the roles of aquaporin-4 in edema resolution 3).

They passively respond to osmotic gradients and play roles in fluid secretion, cell migration, brain edema, metabolism, and many aspects of cell homeostasis 4)

The glymphatic system (or glymphatic clearance pathway) is a functional waste clearance pathway for the mammalian central nervous system (CNS). The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between the CSF and the ISF is driven by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space. Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of the ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.

Results revealed that at 2 hours after cerebral contusion and laceration injury, aquaporin 4 expression significantly increased, brain water content and blood-brain barrier permeability increased, and the number of pinocytotic vesicles in cerebral microvascular endothelial cells increased. In addition, the mitochondrial accumulation was observed. As contusion and laceration injury became aggravated, aquaporin 4 expression continued to increase, brain water content and blood-brain barrier permeability gradually increased, brain capillary endothelial cells and astrocytes swelled, and capillary basement membrane injury gradually increased. The above changes were most apparent at 12 hours after injury, after which they gradually attenuated. Aquaporin 4 expression positively correlated with brain water content and the blood-brain barrier index. This experimental findings indicate that increasing aquaporin 4 expression and blood-brain barrier permeability after cerebral contusion and laceration injury in humans is involved in the formation of brain edema 5).

A article review the vast body of literature on the current understanding of AQP4 channels in relation to hydrocephalus, details regarding molecular aspects of AQP4 channels, possible drug development strategies, and limitations. Advances in medical imaging and computational modeling of CSF dynamics in the setting of hydrocephalus are summarized. Algorithmic developments in computational modeling continue to deepen the understanding of the hydrocephalus disease process and display promising potential benefit as a tool for physicians to evaluate patients with hydrocephalus 6).

Retrospective cohort of 76 aquaporin 4-antibody (AQP4-Ab)-positive patients from Oxford and Liverpool's national NMOSD clinics, assessing current pain and craniocaudal location of cord lesion contemporary to pain onset. (2) Focused prospective study of 26 AQP4-Ab-positive Oxford patients, a subset of the retrospective cohort, assessing current craniocaudal lesion location and current pain.

Patients with isolated thoracic cord myelitis at the time of pain onset were significantly more disabled and suffered more pain. Cervical and thoracic lesions that persisted from pain onset to 'out of relapse' follow-up (current MRI) had highly significant (p<0.01) opposing effects on pain scores (std. β=-0.46 and 0.48, respectively). Lesion length, total lesion burden and number of transverse myelitis relapses did not correlate with pain.

Persistent, caudally located (ie, thoracic) cord lesions in AQP4-Ab-positive patients associate with high postmyelitis chronic pain scores, irrespective of number of myelitis relapses, lesion length and lesion burden. Although disability correlated with pain in isolation, it became an insignificant predictor of pain when analysed alongside craniocaudal location of lesions 7).

Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997 Jan 1;17(1):171-80. PubMed PMID: 8987746.
Bloch O, Manley GT. The role of aquaporin-4 in cerebral water transport and edema. Neurosurg Focus. 2007 May 15;22(5):E3. Review. PubMed PMID: 17613234.
Hsu Y, Tran M, Linninger AA. Dynamic regulation of aquaporin-4 water channels in neurological disorders. Croat Med J. 2015 Oct;56(5):401-21. Review. PubMed PMID: 26526878; PubMed Central PMCID: PMC4655926.
Verkman AS, Anderson MO, Papadopoulos MC. Aquaporins: important but elusive drug targets. Nat Rev Drug Discov. 2014 Apr;13(4):259-77. doi: 10.1038/nrd4226. Epub 2014 Mar 14. Review. PubMed PMID: 24625825; PubMed Central PMCID: PMC4067137.
Li X, Han Y, Xu H, Sun Z, Zhou Z, Long X, Yang Y, Zou L. Aquaporin 4 expression and ultrastructure of the blood-brain barrier following cerebral contusion injury. Neural Regen Res. 2013 Feb 5;8(4):338-45. doi: 10.3969/j.issn.1673-5374.2013.04.006. PubMed PMID: 25206674; PubMed Central PMCID: PMC4107528.
Desai B, Hsu Y, Schneller B, Hobbs JG, Mehta AI, Linninger A. Hydrocephalus: the role of cerebral aquaporin-4 channels and computational modeling considerations of cerebrospinal fluid. Neurosurg Focus. 2016 Sep;41(3):E8. doi: 10.3171/2016.7.FOCUS16191. PubMed PMID: 27581320.
Tackley G, Vecchio D, Hamid S, Jurynczyk M, Kong Y, Gore R, Mutch K, Woodhall M, Waters P, Vincent A, Leite MI, Tracey I, Jacob A, Palace J. Chronic neuropathic pain severity is determined by lesion level in aquaporin 4-antibody-positive myelitis. J Neurol Neurosurg Psychiatry. 2017 Feb;88(2):165-169. doi: 10.1136/jnnp-2016-314991. PubMed PMID: 27884934.
aquaporin_4.txt · Last modified: 2017/02/02 08:11 (external edit)