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Neurosci."],"accepted":{"date-parts":[[2026,8,11]]},"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:p>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) 1 mouse line (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 end feet. 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.<\/jats:p>","DOI":"10.1523\/jneurosci.2184-25.2026","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:55:23Z","timestamp":1787162123000},"page":"e2184252026","update-policy":"https:\/\/doi.org\/10.1523\/jneurosci.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Astrocytic 4R-tau Pathology Drives Aquaporin-4 Mislocalization, Glymphatic Dysfunction, and Neurotransmitter Dysregulation in Mice"],"prefix":"10.1523","volume":"46","author":[{"given":"Menglan","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiuqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renyi","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2026102723502493000_46.40.e2184252026.1","doi-asserted-by":"crossref","unstructured":"Bekdash RA (2021) The cholinergic system, the adrenergic system and the neuropathology of Alzheimer's disease. 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