Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease

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Abstract

Aquaporin-4 (AQP4) is a water channel expressed on astrocytic endfeet in the brain. The role of AQP4 has been studied in health and in a range of pathological conditions. Interest in AQP4 has increased since it was discovered to be the target antigen in the inflammatory autoimmune disease neuromyelitis optica spectrum disorder (NMOSD). Emerging data suggest that AQP4 may also be implicated in the glymphatic system and may be involved in the clearance of beta-amyloid in Alzheimer’s disease (AD). In this review, we will describe the role of AQP4 in the adult and developing brain as well as its implication for disease.

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Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.

G. T. Manley, M Fujimura, T. Ma … (2000)

Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

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Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema.

M Papadopoulos, Sanjeev Krishna, A Verkman … (2004)

Aquaporin-4 (AQP4) is the major water channel in the brain, expressed predominantly in astroglial cell membranes. Initial studies in AQP4-deficient mice showed reduced cellular brain edema following water intoxication and ischemic stroke. We hypothesized that AQP4 deletion would have the opposite effect (increased brain swelling) in vasogenic (noncellular) edema because of impaired removal of excess brain water through glial limitans and ependymal barriers. In support of this hypothesis, we found higher intracranial pressure (ICP, 52+/-6 vs. 26+/-3 cm H2O) and brain water content (81.2+/-0.1 vs. 80.4+/-0.1%) in AQP4-deficient mice after continuous intraparenchymal fluid infusion. In a freeze-injury model of vasogenic brain edema, AQP4-deficient mice had remarkably worse clinical outcome, higher ICP (22+/-4 vs. 9+/-1 cm H2O), and greater brain water content (80.9+/-0.1 vs. 79.4+/-0.1%). In a brain tumor edema model involving stereotactic implantation of melanoma cells, tumor growth was comparable in wild-type and AQP4-deficient mice. However, AQP4-deficient mice had higher ICP (39+/-4 vs. 19+/-5 cm H2O at seven days postimplantation) and corresponding accelerated neurological deterioration. Thus, AQP4-mediated transcellular water movement is crucial for fluid clearance in vasogenic brain edema, suggesting AQP4 activation and/or up-regulation as a novel therapeutic option in vasogenic brain edema.

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Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.

Patrick Waters, A Verkman, Angela Vincent … (2010)

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system associated with autoantibodies against the glial water channel protein aquaporin-4. It has recently been reported that immunoglobulin from neuromyelitis optica patients injected peripherally does not cause lesions in naive rats, but only when pre-existing central nervous system inflammation is present. Here, we investigated whether immunoglobulin G from aquaporin-4-autoantibody-positive neuromyelitis optica patients has the potential to damage the central nervous system either alone or in the presence of human complement. Immunoglobulin G from neuromyelitis optica patients did not activate mouse complement and was not pathogenic when injected into mouse brain. However, co-injection of immunoglobulin G from neuromyelitis optica patients with human complement produced neuromyelitis optica-like lesions in mice. Within 12 h of co-injecting immunoglobulin G from neuromyelitis optica patients and human complement, there was a striking loss of aquaporin-4 expression, glial cell oedema, myelin breakdown and axonal injury, but little intra-parenchymal inflammation. At 7 days, there was extensive inflammatory cell infiltration, perivascular deposition of activated complement components, extensive demyelination, loss of aquaporin-4 expression, loss of reactive astrocytes and neuronal cell death. In behavioural studies, mice injected with immunoglobulin G from neuromyelitis optica patients and human complement into the right hemisphere preferentially turned to the right at 7 days. No brain inflammation, demyelination or right-turning behaviour was seen in wild-type mice that received immunoglobulin G from non-neuromyelitis optica patients with human complement, or in aquaporin-4-null mice that received immunoglobulin G from neuromyelitis optica patients with human complement. We conclude that co-injection of immunoglobulin G from neuromyelitis optica patients with human complement reproduces the key histological features of neuromyelitis optica and that aquaporin-4 is necessary and sufficient for immunoglobulin G from neuromyelitis optica patients to exert its effect. In our mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions.

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Journal

Journal ID (publisher-id): CELLC6

Title: Cells

Abbreviated Title: Cells

Publisher: MDPI AG

ISSN (Electronic): 2073-4409

Publication date Created: February 2019

Publication date (Electronic): January 27 2019

Volume: 8

Issue: 2

Page: 90

Article

DOI: 10.3390/cells8020090

PubMed ID: 30691235

SO-VID: b456b9a3-32a0-4ed8-8f39-2b8a0f1b4ec3

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https://creativecommons.org/licenses/by/4.0/

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Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease

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Most cited references 85

Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke.

Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema.

Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.

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Cited by 76

Most referenced authors 1,631