Astrocyte-driven vasoconstriction impairs glymphatic clearance in a human tauopathy-on-chip model.

The glymphatic system is a critical pathway for clearing metabolic waste from the brain by mediating cerebrospinal fluid and interstitial fluid exchange. In Alzheimer's disease (AD), tau protein accumulation is strongly associated with impaired glymphatic clearance, yet the underlying mechanism remains poorly defined. In this study, we employed a three-dimensional human glymphatics-on-chip model to investigate fluid transport and mass clearance in a brain-mimetic extracellular matrix containing engineered blood vessels (BV) surrounded by primary astrocytes. We found that phosphorylated tau (p-tau) induced morphological transformation of astrocytes into a hypertrophic, hypercontractile state, leading to astrocyte-mediated vasoconstriction and impaired glymphatic clearance. Notably, p-tau did not affect blood endothelial cells directly, implicating astrocyte-dependent mechanisms in glymphatic deregulation. Pharmacological inhibition of non-muscle myosin II with blebbistatin reversed astrocytic hypercontractility, restored BV diameters, and rescued glymphatic function. These findings elucidate a glial-specific mechanism of tau-induced glymphatic dysfunction and underscore astrocytic contractility as a promising therapeutic target in AD.