PVS-Facing AQP4 Transport and Dynamic Inter-Endfoot Gaps Regulate Gap-Dominated Glymphatic Clearance: Implications for Aging

Experimental studies show that impaired aquaporin-4 (AQP4) function or polarization reduces glymphatic clearance, whereas recent mechanical models suggest that pressure-driven water exchange occurs mainly through inter-endfoot gaps rather than directly across the AQP4-rich membrane.

To reconcile these observations, we develop a reduced arterial--ECS--venous multicompartment model coupling vascular forcing, PVS deformation, AQP4-mediated endfoot water exchange, dynamic inter-endfoot gap regulation, and tracer transport.

The model shows that cardiac-like oscillations generate strong bidirectional exchange but weak net clearance, whereas asymmetric vasodilation enhances directional transport by reducing recovery-phase backflow.

Under fixed-gap conditions, the gap-mediated flux is approximately twenty times larger than the direct AQP4-mediated flux.

Nevertheless, AQP4 can strongly regulate clearance indirectly through endfoot-volume feedback and dynamic modulation of gap conductance.

Under symmetric slow-vasomotion forcing, reducing effective AQP4 function decreases cumulative venous output by about \(40\%\).

We further examine aging-associated reductions in vessel motion, altered PVS mechanical coupling, and impaired AQP4 function.

Their combined effects substantially suppress gap opening and venous-directed clearance, reducing cumulative venous output by approximately \(63\%\) and \(74\%\) in representative moderate and advanced aging-like cases.

These results suggest that AQP4 need not carry the dominant hydrostatic flux to regulate clearance, because PVS-facing AQP4 transport alters the hydraulic driving forces of the gap pathway, while endfoot-volume feedback provides an additional modulation of gap conductance.