Every night, the brain flushes out its metabolic waste through a network of fluid-filled channels called the glymphatic system, and this project aims to understand exactly how that process is controlled. The problem is that while scientists know the water channel aquaporin-4 (AQP4) helps drive this waste clearance, and that clearance falters in sleep disorders and neurodegeneration, the mechanical and molecular triggers that turn the system on and off remain unknown. FORTIFY will test the idea that AQP4 molecules physically move in and out of the surface of star-shaped brain cells (astrocytes) in response to sleep-wake changes, thereby widening or narrowing the gaps through which waste-laden fluid flows. If the hypothesis holds, the project will deliver the first complete picture of how brain waste clearance is regulated across the day. This is fundamental science—there is no immediate clinical tool or drug here. But the work includes screening for compounds that shift AQP4 localisation, which could eventually lead to therapies that restore glymphatic function in ageing or dementia. Similar fundamental discoveries about fluid transport in the brain have already reshaped how researchers think about Alzheimer’s disease.
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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.
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