Astrocytic 4R-tau pathology drives aquaporin-4 (AQP4) mislocalization, glymphatic dysfunction, and neurotransmitter dysregulation in mice.

Progressive supranuclear palsy (PSP) is a severe neurodegenerative tauopathy defined by astrocytic tau inclusions and parkinsonism. The link between astrogliopathy and compromised cerebral fluid dynamics remains unclear. We generated a glial fibrillary acidic protein (GFAP)-e (2A-mMAPT(4R) cDNA) transgenic mouse model (GFAP/tau Tg) with astrocyte-specific expression of 4-repeat (4R) tau to investigate mechanisms underlying astrocytic tau pathology as seen in PSP. Both male and female mice were used in this study. GFAP/tau Tg mice exhibited robust astrocytic hyperphosphorylated tau (p-tau) deposition and activation. Mechanistically, this pathology caused dysregulation of the dystrophin-associated complex (DAC), leading to a critical loss of Aquaporin 4 (AQP4) polarity and aberrant AQP4 distribution in perivascular endfeet. This DAC-AQP4 axis disruption critically impaired cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange, subsequently causing deficient glymphatic fluid drainage and excessive ISF accumulation. This fluid stasis was correlated with a significant decline in the synaptic neurotransmitters dopamine (DA) and acetylcholine (ACh). Ultimately, these pathological events manifested as parkinsonian-like motor dysfunction and cognitive deficits in the transgenic mice. Our study clarifies a novel, sequential mechanism linking astrocytic 4R tauopathy to glymphatic circulation failure and neurochemical deficits that recapitulates key astroglial pathological features of PSP. These findings establish the glymphatic system as a compelling therapeutic target for treating neurodegenerative disorders linked to astrogliopathy.Significance Statement Astrocytic 4R-tau pathology is a key pathological feature of progressive supranuclear palsy (PSP) and other tauopathies, but its contribution to glymphatic dysfunction remains unclear. Here we show that astrocyte-specific 4R-tau overexpression in mice drives aquaporin-4 (AQP4) mislocalization, impairs glymphatic flow, and leads to neurotransmitter dysregulation and parkinsonian-like behavioral deficits. These findings establish a direct link between astrocytic tau pathology, glymphatic impairment, and functional neurological decline, highlighting the glymphatic system as a potential therapeutic target for tauopathies featuring astrocytic 4R-tau pathology, including PSP.