Review
Aquaporin and brain diseases,☆☆

https://doi.org/10.1016/j.bbagen.2013.10.032Get rights and content

Highlights

  • Distribution of brain aquaporins and potential functions

  • Role of aquaporin in brain pathologies

  • Aquaporin 4 role in water diffusion and neuroimaging

  • Involvement of brain AQP4 in edema process, neuroinflammation and neurodegenerative diseases

  • Aquaporin and potential treatments

Abstract

Background

The presence of water channel proteins, aquaporins (AQPs), in the brain led to intense research in understanding the underlying roles of each of them under normal conditions and pathological conditions.

Scope of review

In this review, we summarize some of the recent knowledge on the 3 main AQPs (AQP1, AQP4 and AQP9), with a special focus on AQP4, the most abundant AQP in the central nervous system.

Major conclusions

AQP4 was most studied in several brain pathological conditions ranging from acute brain injuries (stroke, traumatic brain injury) to the chronic brain disease with autoimmune neurodegenerative diseases. To date, no specific therapeutic agents have been developed to either inhibit or enhance water flux through these channels. However, experimental results strongly underline the importance of this topic for future investigation. Early inhibition of water channels may have positive effects in prevention of edema formation in brain injuries but at later time points during the course of a disease, AQP is critical for clearance of water from the brain into blood vessels.

General significance

Thus, AQPs, and in particular AQP4, have important roles both in the formation and resolution of edema after brain injury. The dual, complex function of these water channel proteins makes them an excellent therapeutic target. This article is part of a Special Issue entitled Aquaporins.

Section snippets

Aquaporins: subgroups and expression in brain

The aquaporin (AQP) protein family is identified by six membrane spanning domains with intracellular carboxyl (C) and amino (N) termini and a molecular weight around 30 kDa. A common characteristic between all AQP is a consensus motif, Asn-Pro-Ala, which is strongly implicated to play a key role in pore formation [1]. The 13 members of the AQP family are ubiquitously distributed throughout the mammalian tissues and can be categorized into three subgroups: i) Aquaporins (AQP0, 1, 2, 4, 5, 6 and

AQP, water movement and neuroimaging

Diffusion weighted imaging (DWI), T2-weighted imaging (T2WI) and more recently diffusion tensor imaging (DTI) are used for diagnosis/prognosis in patients with brain diseases. The computed T2 value is believed to represent the water content within brain tissues; where increased T2 values correspond to water accumulation in pathological conditions [35]. The quantitative DWI parameter, the apparent diffusion coefficient (ADC), is believed to reflect water mobility within brain tissues.

Edema process: role of the AQPs

Most brain diseases (e.g. stroke, traumatic brain injury, brain tumors, brain inflammation) present the hallmark of edema, which is water accumulation resulting from brain osmotic homeostasis dysfunctions. The main consequence of edema is the swelling of the brain, which aggravates the secondary injuries such as decrease of brain perfusion. Edema has been known in the clinic and pre-clinical science for many years but the molecular and cellular events in edema formation/resolution are still

AQP4 and neuroinflammation in autoimmune and neurodegenerative diseases

Neuroinflammation starts during the acute phase after brain injury and is also present at long term and in chronic brain pathologies like multiple sclerosis (MS). Neuroinflammation is a generic term encompassing complex molecular and cellular events at the BBB among the various brain diseases and injuries [93]. In parallel to microglia activation, astrocytes become activated and play a role in the neuroinflammation process with their involvement in astrogliosis. The role of astrogliosis is

Future developments: drugs against AQP4?

As mentioned previously, there is no specific inhibitor to block the AQP4 channel and such a compound is critical for evaluating the role of AQP4 and treatment of edema. Using siRNA strategy permitted to show the potential to use a specific inhibitor of AQP4 in jTBI and the contribution of astrocytic AQP4 in neuroimaging [54], [61]. Although non-specific, a range of compounds already commercially available that may block AQP4 have been tested. Bumetanide blocks the AQP4 channel and water

Conclusions

The pattern of AQP4 expression during brain disease reveals that AQP4 is a critical component regulating water movement in edema formation and resolution. It is important to note that the role of AQP4 in edema resolution is still unclear and debated. The role of AQP4 in edema formation or resolution might depend on the physiological conditions inducing brain injury. In acute developing injuries like trauma and ischemia, the AQP4 activation pattern seems to be different from more “chronic”

Acknowledgements

A portion of this material was performed in the Loma Linda University School of Medicine Advanced Imaging and Microscopy Core (LLUSM AIM) that is supported by the National Science Foundation under Major Research Instrumentation, Division of Biological Infrastructure Grant No. 0923559 (Sean M Wilson) and the Loma Linda University School of Medicine.

The authors are grateful to Miss Justine Aussudre, INSERM U1049 Bordeaux for excellent technical help. The authors are grateful to Dr Jean-Francois

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    This article is part of a Special Issue entitled Aquaporins.

    ☆☆

    Statement of financial support: This study was supported by grants from the National Institute of Child Disorders (NICHD) R01HD061946 (JB) and Agence Nationale de la Recherche ANR-TecSan 2006-15 “NanoBioImaging”, INSERM 2011 “Precipute”, CNRS BMI 2013 “Pep-Team” and Ligue Française contre la Sclérose En Plaques (LFSEP) (KGP).

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