Heterogeneity of aquaporin-4 localization and expression after focal cerebral ischemia underlies differences in white versus grey matter swelling

Abstract

IntroductionIschemic stroke, a major cause of mortality, is frequently accompanied by life-threatening cerebral edema. Aquaporin-4 (Aqp4), an astrocytic transmembrane water channel, is an important molecular contributor to cerebral edema formation. Past studies of Aqp4 expression and localization after ischemia examined grey matter exclusively. However, as white matter astrocytes differ developmentally, physiologically, and molecularly from grey matter astrocytes, we hypothesized that functionally important regional heterogeneity exists in Aqp4 expression and subcellular localization following cerebral ischemia.ResultsSubcellular localization of Aqp4 was compared between cortical and white matter astrocytes in postmortem specimens of patients with focal ischemic stroke versus controls. Subcellular localization and expression of Aqp4 was examined in rats subjected to experimental stroke. Volumetric analysis was performed on the cortex and white matter of rats subjected to experimental stroke. Following cerebral ischemia, cortical astrocytes exhibited reduced perivascular Aqp4 and unchanged Aqp4 protein abundance. In contrast, white matter astrocytes exhibited increased perivascular and plasmalemmal Aqp4 and a 2.2- to 6.2-fold increase in Aqp4 isoform abundance. Ischemic white matter swelled by approximately 40 %, while cortex swelled by approximately 9 %.ConclusionsThe findings reported here raise the possibility that cerebral white matter may play a heretofore underappreciated role in the formation of cerebral edema following ischemia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0239-6) contains supplementary material, which is available to authorized users.

Gliovascular changes precede white matter damage and long‐term disorders in juvenile mild closed head injury

“…At 1 dpi astrocytic AQP4 was significantly upregulated in both G1 and G2 mice compared to sham mice, but the G1 cohort had significantly increased AQP4 compared to the G2 cohort. The change in AQP4 expression in the WM was observed in the perivascular domain as well as in astrocyte processes (Figure ), similarly to what has been observed in WM but not in gray matter after stroke onset (Stokum et al, ). This suggests a possible conserved mechanism between injuries in the WM.…”

“…We have previously demonstrated the importance of the astrocytic water channel AQP4 in regulation of edema and vascular damage in the cortex after juvenile TBI (Fukuda et al, ). AQP4 has been recently shown to be increased within the WM in association with edema formation (Stokum et al, ). There is an even greater response than in the grey matter (Stokum et al, ).…”

“…AQP4 has been recently shown to be increased within the WM in association with edema formation (Stokum et al, 2015). There is an even greater response than in the grey matter (Stokum et al, 2015).…”

“…AQP4 has been recently shown to be increased within the WM in association with edema formation (Stokum et al, 2015). There is an even greater response than in the grey matter (Stokum et al, 2015). In addition, astrogliosis has been reported in the WM after TBI (Kou & Vande-Vord, 2014) and gliovascular alterations have been proposed as key early events that contribute to lasting consequences of TBI (Jullienne et al, 2016;Kenney et al, 2016;Kou & VandeVord, 2014); however, these studies are mostly performed in moderate-severe adult TBI.…”

Loss of perivascular aquaporin‐4 in idiopathic normal pressure hydrocephalus

“…Loss of AQP4 from perivascular astrocytic endfoot membranes is a key finding in patients with mesial temporal lobe epilepsy (Eid et al, ), neuromyelitis optica (Misu et al, ), ischemic stroke (Steiner et al, ; Stokum et al, ), and Alzheimer's disease (Zeppenfeld et al, ). Numerous studies using animal models conclude that loss or mislocalization of AQP4 affect disease development and survival (Nagelhus & Ottersen, ; Papadopoulos & Verkman, ).…”