FORTIFY - From Molecular Physiology to Biophysics of the Glymphatic System: a Regulatory Role for Aquaporin-4

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The daily clearance of waste products from the brain occurs along perivascular spaces. Fluid flow through this "glymphatic system" is elevated during sleep and its impairment leads to diverse central nervous system (CNS) disorders. Glymphatic exchange is supported by the water channel, aquaporin-4 (AQP4), and is thought to be driven by arterial pulsatility and CNS fluid dynamics that vary throughout the day. However, mechanistic linkages between astroglial transmembrane water flow, cerebrovascular mechanobiology and sleep are unclear. The FORTIFY project will define these linkages and reveal how they control glymphatic function. I will investigate my novel concept that dynamic AQP4 subcellular relocalisation is a master regulator of brain water homeostasis. I hypothesise that sleep-to-wake changes in mechanobiological factors regulate glymphatic flux through the dynamic regulation of AQP4 abundance at the astrocyte cell surface. This in turn controls the gap size between astrocyte endfeet and hence the porosity of the perivascular barrier. Use of a unique "gliovascular interface-on-a-chip" will allow measurement of endfoot morphology, AQP4 abundance and tracer kinetics in response to defined biophysical inputs. In vivo 2-photon imaging will confirm my findings in the living brain. Longitudinal studies in rodent models of impaired amyloid-beta clearance will establish mechanistic links between the regulation of astrocytic AQP4 localisation and dysfunctional CNS waste clearance. My unique compound screens will identify modulators of AQP4 localisation that have potential as future therapeutics to treat cognitive decline. Overall, FORTIFY will create a holistic understanding of glymphatic regulation by bridging molecular and macroscopic control mechanisms. Its experimental outcomes will define how dynamic AQP4 subcellular relocalisation regulates healthy brain waste clearance across the lifespan and will establish novel routes to treat neurodegeneration.