Mou et al. (2010) investigated changes of AQP-4 protein expression in normal brain and in brain glioma tumor and peritumoral edematous tissues and analyzed the relationship of AQP-4 protein with edema index, vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1 alpha (HIF-1α) protein. They demonstrated that expression of AQP-4 was higher in the tumor and highest in the peritumor tissue. Moreover, AQP-4 protein in tumor tissue of gliomas of different grades was not statistically different. In normal brain tissues, AQP-4 was mainly expressed in the foot processes of atsrocytes, but rare in the parenchyma. Finally, the degree of peritumoral edema positively correlated with the expression level of AQP-4 protein and this latter correlated with VEGF and HIF-1α expression. Over-expression of AQP-4 in human meningiomas was associated with significant peritumoral edema. Noël et al. (2012) combining freeze-fracture electron microscopy, immunohistochemistry and Western blotting, described alterations of expression and distribution of AQP-4, dystroglycan, agrin, and matrix metalloproteinases (MMP)-2, -3, and -9 in human primary glioblastomas. They demonstrated an increase in AQP-4 and MMPs expression, and a loss of agrin and dystroglycan expression in glioblastoma compared to control tissue.

AQP-4 knockdown in rat and human astrocytes was associated with a depolymerization of F-actin cytoskeleton with changes of morphology (Nicchia et al. 2005). AQP-4–facilitated astroglial cell migration involves increased plasma membrane osmotic water permeability, which enhances water transport into the cell at its leading edge (Saadoun et al. 2005b). AQP-4 deletion in astroglial cells markedly impaired cell migration toward a stab wound in adult mouse brain and glial scar formation was impaired in AQP-4-null mice with reduced migration of reactive astroglia towards a site of brain injury (Auguste et al. 2007; Saadoun et al. 2005b).

AQP-4 could be also involved in brain tumor migration and invasion and may accelerate glioma migration by facilitating the rapid changes in cell volume that accompany changes in cell shape. We have observed in the peripheral areas of primary tumors isolated glioma cells strongly labeled by AQP-4, indicative of their migratory activity (Nico et al. 2009). Glioma cells show cytoskeleton alterations and a rearrangement of actin filaments (Zhou et al. 2008) and it may be hypothesized that cytoskeleton alterations occurring during glioma transformation induce an up-regulation and mislocalization of AQP-4 favouring tumor cell detachment and migration. Nicchia et al. (2005) have shown that AQP-4 knockdown in rat and human cells was associated with a depolymerization of actin with a change of morphology characterized by a remarkable F-actin cytoskeleton rearrangement in AQP-4 knock-down mouse astrocytes. Moreover, AQP-4 can interact with α-syntrophin, a member of the dystrophin-dystroglycan complex, indicating an involvement of AQP-4 protein in altering the cell cytoskeleton. Accordingly, we have recently demonstrated that in the brain of mdx mouse, an animal model of the Duchenne muscular dystrophy, glial cells showed a significant reduction in both protein and mRNA content of the dystrophin-associated proteins (DAPs), including AQP-4, Kir 4.1, syntrophin and α-β-dystroglycan, coupled with a decrease in dystrophin isoform (Dp71) (Nico et al. 2010). Moreover, we have shown alterations of the vascular basement membrane and reduction of the expression of its components laminin and agrin and trasnslocation of α-β-dystroglycan receptors in the glial cytolasmic endfeet.