Compositions and methods of treatment of tauopathies are provided. In some embodiments, an antagonist of endothclin receptor A (ETA) and endothelin receptor B (ETB) may be administered to a subject to reduce tau production or accumulation, e.g., in astrocytes. The antagonist may be a dual ETA and ETB receptor antagonist. In some aspects, methods are provided for the treatment of chemo-brain, hypoxia, brain ischemia, surgical dementia, glioblastoma, or a traumatic brain injury (TBI).
