AQP4 gene deletion in mice does not alter blood–brain barrier integrity or brain morphology

Academic Neurosurgery Unit, St. George's, University of London, London, UK.
Neuroscience (Impact Factor: 3.36). 05/2009; 161(3):764-72. DOI: 10.1016/j.neuroscience.2009.03.069
Source: PubMed


The glial cell water channel aquaporin-4 (AQP4) plays an important role in brain edema, astrocyte migration, and neuronal excitability. Zhou et al. [Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G (2008) Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport 19:1-5] recently reported that AQP4 deletion significantly altered blood-brain barrier integrity and glial fibrillary acidic protein (GFAP) immunoreactivity in their AQP4 null mice. Here we describe a detailed characterization of baseline brain properties in our AQP4 null mice, including gross appearance, neuronal, astrocyte and oligodendrocyte characteristics, and blood-brain barrier integrity. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood-brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. There were no differences in brain and ventricle sizes between wild type and AQP4 null mice, nor were there differences in the cerebral cortical density of NeuN positive nuclei, perimicrovessel and glia limitans GFAP immunoreactivity, or the thickness and myelination of the corpus callosum. The ultrastructure of microvessels in the frontal cortex and caudate nucleus of wild type vs. AQP4 null mice was indistinguishable, with features including intact endothelial tight junctions, absence of perimicrovessel astrocyte foot process edema, and absence of horseradish peroxidase extravasation. In contrast to the report by Zhou et al. (2008), our data show that AQP4 deletion in mice does not produce major structural abnormalities in the brain.

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    • "In AQP4-null mice unaltered intracranial pressure and compliance were found [142]. Furthermore, no changes in ventricular volume or anatomical features of two different AQP4-null mice strains were reported [143]. However, others observed smaller ventricular sizes, reduced CSF production and increased brain water in AQP4-null mice [144]. "
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    ABSTRACT: According to the traditional understanding of cerebrospinal fluid (CSF) physiology, the majority of CSF is produced by the choroid plexus, circulates through the ventricles, the cisterns, and the subarachnoid space to be absorbed into the blood by the arachnoid villi. This review surveys key developments leading to the traditional concept. Challenging this concept are novel insights utilizing molecular and cellular biology as well as neuroimaging, which indicate that CSF physiology may be much more complex than previously believed. The CSF circulation comprises not only a directed flow of CSF, but in addition a pulsatile to and fro movement throughout the entire brain with local fluid exchange between blood, interstitial fluid, and CSF. Astrocytes, aquaporins, and other membrane transporters are key elements in brain water and CSF homeostasis. A continuous bidirectional fluid exchange at the blood brain barrier produces flow rates, which exceed the choroidal CSF production rate by far. The CSF circulation around blood vessels penetrating from the subarachnoid space into the Virchow Robin spaces provides both a drainage pathway for the clearance of waste molecules from the brain and a site for the interaction of the systemic immune system with that of the brain. Important physiological functions, for example the regeneration of the brain during sleep, may depend on CSF circulation.
    Fluids and Barriers of the CNS 05/2014; 11(1):10. DOI:10.1186/2045-8118-11-10
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    • "AQP4-knockout mice suffer from vasogenic brain edema [35], [36]. Saadoun et al. found that deletion of AQP4 in mice does not produce major structural abnormalities in the brain [37]. Moreover, Bonomini and Rezzani reported the relationship between aquaporin and BBB and suggested that AQP4 deficiency may reduce cytotoxic edema, but increase vasogenic edema [38]. "
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    ABSTRACT: Treadmill pre-training can ameliorate blood brain barrier (BBB) dysfunction in ischemia-reperfusion injury, however, its role in ischemic brain edema remains unclear. This study assessed the neuroprotective effects induced by treadmill pre-training, particularly on brain edema in transient middle cerebral artery occluded model. Transient middle cerebral artery occlusion to induce stroke was performed on rats after 2 weeks of treadmill pre-training. Magnetic resonance imaging (MRI) was used to evaluate the dynamic impairment of cerebral edema after ischemia-reperfusion injury. In addition, measurements of wet and dry brain weight, Evans Blue assay and Garcia scores were performed to investigate the cerebral water content, BBB permeability and neurologic deficit, respectively. Moreover, during ischemia-reperfusion injury, the expression of Aquaporin 4 (AQP4) was detected using immunofluorescence and Western bloting analyses. Treadmill pre-training improved the relative apparent diffusion coefficient (rADC) loss in the ipsilateral cortex and striatum at 1 hour and 2.5 hours after cerebral ischemia. In the treadmill pre-training group, T2W1 values of the ipsilateral cortex and striatum increased less at 7.5 hours, 1 day, and 2 days after stroke while the brain water content decreased at 2 days after ischemia. Regarding the BBB permeability, the semi-quantitative amount of contrast agent leakage of treadmill pre-training group significantly decreased. Less Evans Blue exudation was also observed in treadmill pre-training group at 2 days after stroke. In addition, treadmill pre-training mitigated the Garcia score deficits at 2 days after stroke. Immunofluorescence staining and Western blotting results showed a significant decrease in the expression of AQP4 after treadmill ischemia following pre-training. Treadmill pre-training may reduce cerebral edema and BBB dysfunction during cerebral ischemia/reperfusion injury via the down-regulation of AQP4.
    PLoS ONE 01/2014; 9(1):e84602. DOI:10.1371/journal.pone.0084602 · 3.23 Impact Factor
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    • "During a middle cerebral artery occlusion (MCAO), a mouse model of stroke, Aqp4 deficient mice have a decreased cytotoxic cerebral edema and therefore an improved neurological outcome [143]. Saadoun et al. showed that Aqp4 deficient mice have a morphologically and functionally normal BBB [144]. Therefore it appears that Aqp4 plays a key role in brain swelling during pathology, but not in normal BBB architecture. "
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    ABSTRACT: The blood–brain barrier (BBB) is a complex physiological structure formed by the blood vessels of the central nervous system (CNS) that tightly regulates the movement of substances between the blood and the neural tissue. Recently, the generation and analysis of different genetic mouse models has allowed for greater understanding of BBB development, how the barrier is regulated during health and its response to disease. Here we discuss: 1) Genetic mouse models that have been used to study the BBB, 2) Available mouse genetic tools that can aid in the study of the BBB, and 3) Potential tools that if generated could greatly aid in our understanding of the BBB.
    Fluids and Barriers of the CNS 01/2013; 10(1):3. DOI:10.1186/2045-8118-10-3
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