Inhibition of astrocytic AT1R ameliorates sleep deprivation induced Aβ deposition and glymphatic dysfunction via the MAPK/Cx43 pathway

Oct 17, 2025Sleep medicine

Blocking a specific receptor in support brain cells may reduce sleep loss-related protein buildup and waste clearance problems through a cell communication pathway

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Abstract

Upregulation of astrocytic AT1R and amyloid-beta levels was observed in the hippocampus of chronic sleep deprivation model animals.

Astrocytic AT1R may play a role in cognitive deficits associated with sleep deprivation.
Inhibiting astrocytic AT1R alleviated cognitive impairments and increased amyloid-beta levels in sleep-deprived mice.
Disruption of the glymphatic system may be linked to sleep deprivation pathology, involving altered localization of aquaporin-4.
Knockout of astrocytic AT1R improved glymphatic function and restored perivascular localization of aquaporin-4 in sleep-deprived mice.
The MAPK/Cx43 pathway may regulate the distribution of aquaporin-4 through astrocytic AT1R.

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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.

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Inhibition of astrocytic AT1R ameliorates sleep deprivation induced Aβ deposition and glymphatic dysfunction via the MAPK/Cx43 pathway

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