A Microfluidic Model of AQP4 Polarization Dynamics and Fluid Transport in the Healthy and Inflamed Human Brain: The First Step Towards Glymphatics-on-a-Chip

Dysfunction of the aquaporin-4 (AQP4)-dependent glymphatic waste clearance pathway has recently been implicated in the pathogenesis of several neurodegenerative diseases. However, it is difficult to unravel the causative relationship between glymphatic dysfunction, AQP4 depolarization, protein aggregation, and inflammation in neurodegeneration using animal models alone. There is currently a clear, unmet need for in vitro models of the brain's waterscape, and the first steps towards a bona fide glymphatics-on-a-chip are taken in the present study. It is demonstrated that chronic exposure to lipopolysaccharide (LPS), amyloid-beta(1-42) oligomers, and an AQP4 inhibitor impairs the drainage of fluid and amyloid-beta(1-40) tracer in a gliovascular unit (GVU)-on-a-chip model containing human astrocytes and brain microvascular endothelial cells. The LPS-induced drainage impairment is partially retained following cell lysis, indicating that neuroinflammation induces parallel changes in cell-dependent and matrisome-dependent fluid transport pathways in GVU-on-a-chip. Additionally, AQP4 depolarization is observed following LPS treatment, suggesting that LPS-induced drainage impairments on-chip may be driven in part by changes in AQP4-dependent fluid dynamics.

Automated summary

This study demonstrates for the first time the impairment of fluid and amyloid-beta drainage in a gliovascular unit-on-a-chip model due to chronic exposure to LPS, amyloid-beta(1-42) oligomers, and an AQP4 inhibitor. The findings suggest that neuroinflammation induces changes in both cell-dependent and matrisome-dependent fluid transport pathways, and AQP4 depolarization may play a role in the observed drainage impairments on-chip.