Sleep deprivation (SD) is strongly correlated to the cognitive deficits and is a major factor for Alzheimer's disease (AD). Clinical studies suggested that Ang II receptor1 (AT1R) blockers significantly reduced the prevalence of AD. However, the role and molecular mechanisms of ATIR in SD is still unknown. In present study, we identified an upregulation of astrocytic AT1R and amyloid-beta (Aβ) levels in the hippocampus of chronic SD model animals. We then used astrocyte-specific knockout AT1R (AT1R-/-) mice to evaluate the effects of astrocytic AT1R in SD. Our findings revealed that inhibiting astrocytic AT1R ameliorated SD induced cognitive deficits and increased Aβ levels. Emerging evidence suggested that impaired Aβ clearance by the glymphatic system (GS) contributed to SD pathology, involving disrupted localization of aquaporin-4 (AQP4), a water channel predominantly expressed on astrocytic endfeet surrounding blood vessels. Notably, we found that specific knockout astrocytic AT1R restored glymphatic dysfunction and improved perivascular AQP4 localization in SD mice. Furthermore, using MAPK inhibitor PD98059 both in vivo and in vitro, we demonstrated astrocytic AT1R regulated AQP4 hyperplasia distribution via MAPK/Cx43 pathway in astrocytes. Collectively, our findings reveal a direct contribution of astrocytic AT1R in SD by modulating GS clearance mediated by the perivascular AQP4 localization, highlighting its potential as a novel preventive or therapeutic target for cognitive disorders associated with SD.
