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Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis

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Salman, Mootaz M, Kitchen, Philip, Halsey, Andrea, Wang, Marie Xun, Törnroth-Horsefield, Susanna, Conner, Alex C, Badaut, Jerome, Iliff, Jeffrey J +1 more·2022·Brain
DOI 10.1093/brain/awab311PMC PMC9088512
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Abstract

Aquaporin channels facilitate bidirectional water flow in all cells and tissues. AQP4 is highly expressed in astrocytes. In the CNS, it is enriched in astrocyte endfeet, at synapses, and at the glia limitans, where it mediates water exchange across the blood–spinal cord and blood–brain barriers (BSCB/BBB), and controls cell volume, extracellular space volume, and astrocyte migration. Perivascular enrichment of AQP4 at the BSCB/BBB suggests a role in glymphatic function. Recently, we have demonstrated that AQP4 localization is also dynamically regulated at the subcellular level, affecting membrane water permeability. Ageing, cerebrovascular disease, traumatic CNS injury, and sleep disruption are established and emerging risk factors in developing neurodegeneration, and in animal models of each, impairment of glymphatic function is associated with changes in perivascular AQP4 localization. CNS oedema is caused by passive water influx through AQP4 in response to osmotic imbalances. We have demonstrated that reducing dynamic relocalization of AQP4 to the BSCB/BBB reduces CNS oedema and accelerates functional recovery in rodent models. Given the difficulties in developing pore-blocking AQP4 inhibitors, targeting AQP4 subcellular localization opens up new treatment avenues for CNS oedema, neurovascular and neurodegenerative diseases, and provides a framework to address fundamental questions about water homeostasis in health and disease.

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  • Under pathological conditions, astrocytes undergo reactive astrogliosis characterized by morphological and functional changes such as hypertrophy, process elongation, up-regulation of GFAP, or dynamic relocalization of proteins such as aquaporin-4.

    “Under pathological conditions, they undergo reactive astrogliosis, characterized by morphological and functional changes such as hypertrophy, process elongation, up-regulation of glial fibrillary acidic protein (GFAP) (2–5), or dynamic relocalization of proteins such as aquaporin-4 (6, 7).”

    From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [7]

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Authors
Salman, M. M., Kitchen, P., Halsey, A., Wang, M. X., Törnroth-Horsefield, S., Conner, A. C., Badaut, J., Iliff, J. J., & Bill, R. M.
Affiliations
  • University of Oxford (GB)
  • Aston University (GB)
  • University of Birmingham (GB)
  • University of Washington (US)
  • Department of Biochemistry and Structural Biology, Lund University, PO Box 124, 221 00 Lund, Sweden
  • CNRS-UMR 5536-Centre de Résonance Magnétique des systèmes Biologiques, Université de Bordeaux, 33076 Bordeaux, France
Corresponding author
  • Salman, Mootaz M
  • Kitchen, Philip
  • Bill, Roslyn M
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2021-09-09
Volume
145
Issue
1
Pages
64-75
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awab311
PMC
PMC9088512
OpenAlex
W3198642554
Cited by
303
References
11
Citations by year
2026: 85 · 2025: 60 · 2024: 58 · 2023: 50 · 2022: 38 · 2021: 12
FWCI
12.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Aston Publications Explorer (Aston University) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Biotechnology and Biosciences Research Council (BB/P025927/1)
  • Aston University
  • Swedish Research Council (2013–05945)
  • Crafoord Foundation (20140811 and 20180916)
  • Magnus Bergvall Foundation (2015–01534)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
aquaporin-4, subcellular relocalization, glymphatic system, blood-brain barrier, blood-spinal cord barrier, astrocytes, membrane water permeability, neurodegeneration, cerebrovascular disease, traumatic brain injury, sleep disruption, aging, astrocyte migration, extracellular space volume
MeSH terms
Animals, Astrocytes, Blood-Brain Barrier, Homeostasis, Humans, Water, Aquaporin 4

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