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Aquaporin 4 and glymphatic flow have central roles in brain fluid homeostasis

Nature Reviews Neuroscience volume 22, pages 650–651 (2021)Cite this article

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In their recent Review (MacAulay, N. Molecular mechanisms of brain water transport. Nat. Rev. Neurosci. 22, 326–344 (2021))1, MacAulay highlights many open questions about how brain water transport is controlled. They posit that cotransport of water may bridge the gap in our understanding of cellular and barrier brain water transport. As the existence of the glymphatic system and its dependence upon the glial water channel aquaporin 4 (AQP4) have been controversial, MacAulay places them outside the scope of their Review. We agree that a lack of mechanistic insight into them represents a significant gap in current knowledge of the brain in health and disease. However, it is necessary to contextualize the role of AQP4 in glymphatic function (which we think deserves more attention) and address the need for tighter definitions when describing the fluids involved. As MacAulay’s review has such a broad title, our aim is to provide its reader with an appreciation of these important and, in some cases, emerging concepts in brain fluid dynamics.

A comprehensive view of brain water transport must include the role of the glymphatic system (which refers to perivascular and paracellular fluid transport (Fig. 1)), especially in light of recent studies suggesting that perivascular cerebrospinal fluid (CSF) is a major source of oedema fluid that accumulates acutely following stroke3. The AQP4 dependence of perivascular flow is established: work in five independent laboratories4 has refuted the single study5 suggesting that this is an AQP4-independent process. The link between AQP4 and glymphatic function is compelling, not only from studies in Aqp4–/– mice, but also Snta1–/– and mdx mice. Together, these studies confirm a requirement for polarized AQP4 localization for rapid tracer transport from the CSF into the brain parenchyma. We agree with MacAulay’s view that a biophysical explanation for how AQP4 at astrocyte endfeet indirectly facilitates glymphatic flux is incompletely understood. However, we have shown that subcellular relocalization of AQP4, from intracellular vesicles to the plasma membrane, has a crucial role in the regulation of AQP4 function6 (Fig. 1). We6 and others7,8 have also shown that AQP4 subcellular relocalization is a dynamic process independent of changes in AQP4 expression. Following pathological dysregulation, AQP4 relocalization to astrocyte endfeet facilitates oedema formation, which can be pharmacologically inhibited6. A comprehensive review of brain water transport should therefore consider the dynamic relocalization of AQP4 channels as it provides a framework to address fundamental questions about water homeostasis in health and disease.

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Fig. 1: Aquaporin 4 has direct and indirect roles in controlling fluid flow in the brain.

References

  1. MacAulay, N. Molecular mechanisms of brain water transport. Nat. Rev. Neurosci. 22, 326–344 (2021).

    Article  CAS  Google Scholar 

  2. Alshuhri, M. S., Gallagher, L., Work, L. M. & Holmes, W. M. Direct imaging of glymphatic transport using H217O MRI. JCI Insight 6, e141159 (2021).

    Article  Google Scholar 

  3. Mestre, H. et al. Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science 367, eaax7171 (2020).

    Article  CAS  Google Scholar 

  4. Mestre, H. et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7, e40070 (2018).

    Article  Google Scholar 

  5. Smith, A. J., Yao, X., Dix, J. A., Jin, B.-J. & Verkman, A. S. Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. eLife 6, e27679 (2017).

    Article  Google Scholar 

  6. Kitchen, P. et al. Targeting aquaporin-4 subcellular localization to treat central nervous system edema. Cell 181, 784–799 (2020).

    Article  CAS  Google Scholar 

  7. Ciappelloni, S. et al. Aquaporin-4 surface trafficking regulates astrocytic process motility and synaptic activity in health and autoimmune disease. Cell Rep. 27, 3860–3872 (2019).

    Article  CAS  Google Scholar 

  8. Lisjak, M., Potokar, M., Rituper, B., Jorgačevski, J. & Zorec, R. AQP4e-based orthogonal arrays regulate rapid cell volume changes in astrocytes. J. Neurosci. 37, 10748–10756 (2017).

    Article  CAS  Google Scholar 

  9. Yang, B., Zhang, H. & Verkman, A. S. Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides. Bioorg. Med. Chem. 16, 7489–7493 (2008).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Mootaz M. Salman

  2. Oxford Parkinson’s Disease Centre, University of Oxford, Oxford, UK

    Mootaz M. Salman

  3. School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, UK

    Philip Kitchen & Roslyn M. Bill

  4. Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA

    Jeffrey J. Iliff

  5. Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

    Jeffrey J. Iliff

  6. VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA

    Jeffrey J. Iliff

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Correspondence to Mootaz M. Salman, Philip Kitchen, Jeffrey J. Iliff or Roslyn M. Bill.

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Nature Reviews Neuroscience thanks R. Keep and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Salman, M.M., Kitchen, P., Iliff, J.J. et al. Aquaporin 4 and glymphatic flow have central roles in brain fluid homeostasis. Nat Rev Neurosci 22, 650–651 (2021). https://doi.org/10.1038/s41583-021-00514-z

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