Protective role of brain water channel AQP4 in murine cerebral malaria

Abstract

Tragically common among children in sub-Saharan Africa, cerebral malaria is characterized by rapid progression to coma and death. In this study, we used a model of cerebral malaria appearing in C57BL/6 WT mice after infection with the rodent malaria parasite Plasmodium berghei ANKA. Expression and cellular localization of the brain water channel aquaporin-4 (AQP4) was investigated during the neurological syndrome. Semiquantitative real-time PCR comparing uninfected and infected mice showed a reduction of brain AQP4 transcript in cerebral malaria, and immunoblots revealed reduction of brain AQP4 protein. Reduction of brain AQP4 protein was confirmed in cerebral malaria by quantitative immunogold EM; however, polarized distribution of AQP4 at the perivascular and subpial astrocyte membranes was not altered. To further examine the role of AQP4 in cerebral malaria, WT mice and littermates genetically deficient in AQP4 were infected with P. berghei. Upon development of cerebral malaria, WT and AQP4-null mice exhibited similar increases in width of perivascular astroglial endfeet in brain. Nevertheless, the AQP4-null mice exhibited more severe signs of cerebral malaria with greater brain edema, although disruption of the blood-brain barrier was similar in both groups. In longitudinal studies, cerebral malaria appeared nearly 1 d earlier in the AQP4-null mice, and reduced survival was noted when chloroquine rescue was attempted. We conclude that the water channel AQP4 confers partial protection against cerebral malaria. C erebral malaria is a dangerous complication of infection with Plasmodium falciparum, especially in children of sub-Saharan Africa, with a mortality rate of 20% (1). If untreated, cerebral malaria often causes coma and death within 24 h (2). Survivors of cerebral malaria often suffer neurological sequelae such as ataxia, hemiplegia, epilepsy, and blindness. The exact pathogenesis of cerebral malaria remains unclear. It is thought that massive sequestration of erythrocytes containing mature stages of P. falciparum within the brain microvasculature (3), as well as an excessive response of the host immune system against the malaria parasite, contribute to the disease (4).Brain edema and intracranial hypertension are common in cerebral malaria. Elevated cerebrospinal fluid pressure has been reported in more than 80% of African children with cerebral malaria (5, 6). Computed tomography of Kenyan children with cerebral malaria revealed that more than 40% had brain edema (7). More recently, increased brain volume in Malawian children with cerebral malaria based on MRI was reported (8). Severe intracranial hypertension in children with cerebral malaria is often fatal (7, 9). Autopsies of African children who died from cerebral malaria revealed brain edema (10, 11).A murine model of cerebral malaria has been established in a susceptible strain of mice (C57BL/6) infected with the rodent malaria parasite P. berghei ANKA (12). Although relevance to human cerebral malaria in adults has been questioned (13), this mo...

Subcellular expression of aquaporin-4 in substantia nigra of normal and MPTP-treated mice

“…In both conditions gliosis is associated with a loss rather than an increase of endfoot AQP4 (Eid et al 2005;Yang et al 2011). Also in a model of cerebral malaria there is an overall decrease in AQP4 expression, despite extensive gliosis (Promeneur et al 2013). Further studies are needed to unravel the mechanistic link between AQP4 expression and proneness to PD and -in a longer time perspective -to ascertain whether astrocytes could serve as targets of new therapies.…”

CD8+ T Cells Induce Fatal Brainstem Pathology during Cerebral Malaria via Luminal Antigen-Specific Engagement of Brain Vasculature

“…These include increased pro-inflammatory cytokines, vascular pathology, disruption of the BBB, and cerebral edema [16–19]. ECM in mice is a widely used model of HCM and provides a valuable tool for elucidating the mechanisms involved in CM pathogenesis and identifying cellular and molecular targets for adjunctive therapy [20].…”

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…In this model, Aqp4 -/-mice showed reduced edema, improved neurological status and increased survival. On the other hand, reduction of AQP4 has also been described in inflammatory diseases, including cerebral malaria (341), where Aqp4 -/-exhibited more severe signs of cerebral malaria as well as brain edema, demonstrating a protective role of AQP4. These data clearly point to a role of AQP4 in neuroinflammation, although it remains unclear how it mediates this process and whether it is beneficial or detrimental.…”

“…However, evidence for changes in the number or astrocyte reactivity in postmortem brains of PD patients is inconsistent (185,187), and gliosis has been shown to be more prominent in models of PD than in patients (186). Notably, upregulation of AQP4 is not necessarily co-localized with GFAP expression, as shown in a mouse model of ALS (348), and GFAP upregulation is not automatically accompanied by an increase in AQP4, evident in a model of cerebral malaria (341). This indicates that AQP4 expression is not linearly related to GFAP.…”

“…Aqp4 -/-mice have exhibited reduced survival in vasogenic edema associated with tumor, cold brain injury and persistent ischemia compared to WTs (451, 458, 459), more severe signs of cerebral malaria (341), and less clearance of amyloid-β by the glymphatic system (320), indicating that AQP4 may contribute to plaque formation in AD. In four studies by the same group, Aqp4 -/-mice were more prone to MPTPinduced neurotoxicity in acute and chronic models of PD (352)(353)(354)(355).…”