Aquaporin 4: A Player in Cerebral Edema and Neuroinflammation

Andrew M Fukuda; Jerome Badaut


J Neuroinflammation. 2012;9(279) 

In This Article

General introduction

Aquaporin 4 - Overview

Aquaporin (AQP) is a family of water channel protein ubiquitously expressed in various cell types and organisms.[13] The aquaporin family exhibits a common structure with six membrane spanning alpha helical domains, a consensus motif composed of Asparagine-Proline-Alanine (NPA) constituting part of the pore, and an approximate molecular weight of 30 kDa.[14] AQP4 is the most abundant AQP found in the primate and rodent brains, mainly in the perivascular astrocyte endfeet.[13] AQP4 is assembled in homo-tetramers where each individual aquaporin represents a water channel (Figure 1A).[15] The assemblage of four molecules of AQP4 forms a central pore, through which water, cations, and gases such as CO2 flow.[16] Interestingly, AQP4 proteins are major constituents of a higher structural arrangement within astrocyte endfoot named the orthogonal arrays of particles (OAPs) observed using electron microscopy after cryo-fracture preparation[17] (Figure 1B). The size of the OAPs is determined by the ratio between the two main isoforms of AQP4: the long (AQP4-m1) and short (AQP4-m23) splice variants (Figure 1B).[17] The AQP4-m23 isoform stabilizes the OAP structure.[17,18] The exact functional roles of the OAPs remain unknown both in normal and pathological brains. An increase in the AQP4 m1 variant disrupts the structure of the OAPs,[17,18] which is observed in stroke[19,20] and parallels blood–brain barrier (BBB) disruption. The role of AQP4 within the perivascular space and in BBB structure is still a matter of discussion and unresolved.[21,22] Interestingly, OAPs were proposed to play a role in potassium buffering.[23,24] Strengthening this hypothesis, AQP4 found in the astrocyte endfeet facing cerebral blood vessels co-localized with the potassium channel, Kir4.1.[25,26] AQP4 knockout mice (AQP4−/−) showed a delay in potassium reuptake suggesting that AQP4 has a role in potassium homeostasis in facilitating water diffusion along the potassium gradient during brain activity.[27] Not only involved in water movement, AQP4 may also contribute to cell adhesion[28] and migration.[29] These data underline the diversity and complexity in AQP4 functions, and the subsequent sections will show another possible function of AQP4 in the process of neuroinflammation.

Figure 1.

Structural organization of AQP4 in the astrocyte membrane. (A) Schematic drawing of the AQP4 homo-tetramer assembly within the lipid membrane from a lateral view resulting in a central pore permeable to cations and gases (green arrows).16 Each individual aquaporin facilitates bi-directional water movement that is dependent on the osmotic gradient (blue arrows) (modified from Badaut et al.57). (B) In normal brain, association between AQP4-m1 (red circles) and AQP4-m23 (blue circles) isoforms contribute to form orthogonal array of particles (OAPs). Higher expression of AQP4-m23 contributes to the formation of large OAPs, and should facilitate the gas, ion (green arrows), and water diffusion (water arrows) through the astrocyte membrane. (C) In brain injury, increase of AQP4-m119 should contribute to disruption of OAPs (modified from Badaut et al.57). Changes in OAP size may decrease the number of central pore and possibly affect not only water movement but also the ion and gas movements.

Microglia, Astrocytes, and AQP4 in the Context of Neuroinflammation

Neuroinflammation is largely described in the acute phase after brain injury, along with edema, as well as in chronic brain diseases like multiple sclerosis. The term, 'neuroinflammation', encompasses several molecular and cellular modifications without a clear, unified definition amongst the various brain diseases and injuries. However, it is important to realize that neuroinflammation is distinct from peripheral inflammation,[30–32] even if they share some of the same molecular players, particularly due to microglia and astrocytes, which are cells specific to the CNS. Since the inflammatory process may differ from organ to organ,[31] Graeber and colleagues recently drew the attention to the potential danger of using the two terminologies 'neuroinflammation' and 'inflammation' interchangeably.

Although microglia is the cell type considered to be primarily responsible for the innate immune response in the CNS,[33,34] it is premature to conclude that a decrease in microglial activation is the only evidence needed for the treatment of neuroinflammation with anti-inflammatory drugs.[30] Activation status for both astrocytes and microglia, along with secretion of cytokines and chemokines, should be considered for neuroinflammation. Microglial activation is characterized by morphological changes in which the usually ramified microglia becomes round with no ramifications.[33] There seems to be a dual role for microglial activation in which acute activation is beneficial[35] but a chronic one is detrimental.[33,36] In fact, activated microglia is responsible for producing pro-inflammatory cytokines such as IL-1β, IL-6, TNFα and also anti-inflammatory cytokines such as IL-4, IL-10 and TFGβ.[37]

Activated astrocytes also play a key role in neuroinflammation with their involvement in astrogliosis, although whether astrogliosis is beneficial or detrimental seem to depend on the situation,[38] much like microglial activation. The process of astrogliosis includes the hyptertrophy of astrocytes with different morphological fates depending on the severity of the injury.[39] The absence of AQP4 in astrocytic endfeet may lead to decreased hypertrophy of astrocytes due to decreased water entry and migration toward the site of the injury.[29,40] Like microglia, activated astrocytes contribute to the secretion of chemokines and cytokines (see examples above), possibly involved in BBB disruption and vasogenic edema. Interestingly, AQP4 is upregulated in the vasogenic edema resolution phase visualized by normalization of magnetic resonance (MR) signals in several disease models.[2,41] Furthermore, AQP4 has also been reported to be present in reactive microglia after intranigral injection of lipopolysaccharide (LPS) in rats, although the functional significance of this de novo microglial AQP4 expression is unknown.[42] These changes in AQP4 during the inflammatory process suggest changes in water movement related to neuroinflammation.