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

Saadoun, Samira; Tait, Matthew; Reza, Abbas; Davies, D.C.; Bell, B. Anthony; Verkman, A. S.; Papadopoulos, Marios C.

doi:10.1016/j.neuroscience.2009.03.069

Cited by 110 publications

(90 citation statements)

References 30 publications

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“…No evidence was found of such a mechanism, as extravasation of Evans blue did not differ between genotypes. Our data on Evans blue extravasation are in line with those reported for constitutive Aqp4 −/− mice (24).…”

Section: Discussionsupporting

confidence: 92%

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

Haj-Yasein

Vindedal

Eilert-Olsen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

285

264

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Tissue-and cell-specific deletion of the Aqp4 gene is required to differentiate between the numerous pools of aquaporin-4 (AQP4) water channels. A glial-conditional Aqp4 knockout mouse line was generated to resolve whether astroglial AQP4 controls water exchange across the blood-brain interface. The conditional knockout was driven by the glial fibrillary acidic protein promoter. Brains from conditional Aqp4 knockouts were devoid of AQP4 as assessed by Western blots, ruling out the presence of a significant endothelial pool of AQP4. In agreement, immunofluorescence analysis of cryostate sections and quantitative immunogold analysis of ultrathin sections revealed no AQP4 signals in capillary endothelia. Compared with litter controls, glial-conditional Aqp4 knockout mice showed a 31% reduction in brain water uptake after systemic hypoosmotic stress and a delayed postnatal resorption of brain water. Deletion of astroglial Aqp4 did not affect the barrier function to macromolecules. Our data suggest that the blood-brain barrier (BBB) is more complex than anticipated. Notably, under certain conditions, the astrocyte covering of brain microvessels is rate limiting to water movement. edema | electron microscopy | homeostasis | membrane | swelling M ore than 100 y have elapsed since it was first shown that some solutes present in blood are retained by brain capillaries, pointing to the existence of a barrier function at the bloodbrain interface. This early finding naturally inspired a discussion as to what could constitute the morphological substrate of this barrier (1). With the advent of the electron microscope it became clear that the blood-brain interface is composed of endothelia and pericytes, surrounded by a basal lamina and perivascular endfeet of astrocytes. After decades of intense debate, a concept emerged that the functional barrier resides at the level of the endothelial cells (2). This was consistent with morphological data, which clearly showed that endothelia were continuous and coupled by tight junctions (3). The perivascular endfeet, on the other hand, were not coupled by tight junctions and were portrayed as a discontinuous layer with spacious clefts separating the individual processes.Discussions on the morphological substrate of barrier function have been focused on solutes (4), and the field has not yet matured to provide a consistent view regarding what cellular structures, if any, restrict water movement between blood and brain. Following the discovery of water channels, it became clear that the major brain water channel AQP4 is implicated in water transport at the blood-brain interface. Thus, global Aqp4 knockout significantly limited the development of brain edema, attesting to the importance of AQP4 water channels (4). As AQP4 is strongly expressed in the perivascular endfeet (5), the interest in these processes was rekindled also in the context of their possible barrier function.Specifically, it was proposed that the endfeet could restrict water flow, most significantly in pathophysiological se...

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Section: Discussionsupporting

confidence: 92%

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

Haj-Yasein

Vindedal

Eilert-Olsen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

285

264

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“…This finding was obtained under nonphysiological conditions, but nevertheless is in line with the concept that AQP4 controls brain interstitial water resorption. It is notable that deletion of Aqp4 does not alter blood-brain barrier (BBB) integrity, as reported in two of the three Aqp4 Ϫ/Ϫ lines that are currently available (34,167). In the third line, Zhou et al (215) concluded that Aqp4 deletion did interfere with BBB integrity, although this could not be reproduced in a more recent study of this line (167).…”

Section: Saline Infusion In Brains Of Aqp4mentioning

confidence: 93%

Physiological Roles of Aquaporin-4 in Brain

Nagelhus

Ottersen

2013

Physiological Reviews

576

520

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(AQP4) is one of the most abundant molecules in the brain and is particularly prevalent in astrocytic membranes at the blood-brain and brain-liquor interfaces. While AQP4 has been implicated in a number of pathophysiological processes, its role in brain physiology has remained elusive. Only recently has evidence accumulated to suggest that AQP4 is involved in such diverse functions as regulation of extracellular space volume, potassium buffering, cerebrospinal fluid circulation, interstitial fluid resorption, waste clearance, neuroinflammation, osmosensation, cell migration, and Ca 2ϩ signaling. AQP4 is also required for normal function of the retina, inner ear, and olfactory system. A review will be provided of the physiological roles of AQP4 in brain and of the growing list of data that emphasize the polarized nature of astrocytes.

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“…Such abnormalities are not in line with other studies on Aqp4 knockout animals (292,311,312). Although AQP4 potentially could increase cell survival, in line with the glymphatic system theory (320), it is unlikely to be responsible for reduced neuroinflammation as the CNS diffusion of inflammatory cells and soluble factors seems to be increased, rather than reduced, by AQP4 (338).…”

Section: Selective Vulnerability Mediated By the Glial Microenvironmementioning

confidence: 81%

“…Moreover, glial-conditional Aqp4 knockouts demonstrate delayed postnatal reabsorption of water, resulting in slightly higher brain water content in Aqp4 knockout animals (164). Although removal of AQP4 itself does not result in impaired water homeostasis (292,311,312), AQP4 has been demonstrated to play a key role in several pathological conditions associated with water accumulation in brain tissue, known as brain edema. As the cranium forms a physical constriction to swelling, increased intracranial pressure is lethal.…”

Section: Control Of Water Flux and Brain Edemamentioning

confidence: 99%

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

et al. 2011

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

Cited by 110 publications

References 30 publications

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

Glial-conditional deletion of aquaporin-4 ( Aqp4 ) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet

Physiological Roles of Aquaporin-4 in Brain

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

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