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

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.

Kitchen, PhilipAston University (författare)
Halsey, AndreaUniversity of Birmingham (författare)
Wang, Marie XunWashington University School of Medicine (författare)
Törnroth-Horsefield, SusannaLund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)bioc-sst (författare)
Conner, Alex C.University of Birmingham (författare)
Badaut, Jerome (författare)
Iliff, Jeffrey J.VA Puget Sound Health Care System,Washington University School of Medicine (författare)
Bill, Roslyn M.Aston University (författare)
University of OxfordAston University (creator_code:org_t)

Av författaren/redakt...: Salman, Mootaz M ...; Kitchen, Philip; Halsey, Andrea; Wang, Marie Xun; Törnroth-Horsefi ...; Conner, Alex C.; visa fler...; Badaut, Jerome; Iliff, Jeffrey J ...; Bill, Roslyn M.; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Neurovetenskaper

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