Astrocytic AT1R deficiency ameliorates Aβ-induced cognitive deficits and synaptotoxicity through β-arrestin2...

Alzheimer's disease (AD) seriously influences human health, and there is no effective treatment to prevent or cure AD. Recent studies have shown that angiotensin II type 1 receptor (AT1R) blockers significantly reduce the prevalence of AD, while the precise role and mechanism of AT1R in AD remain obscure. In this study, for the first time, we identified that astrocytic but not neuronal AT1R levels were significantly increased in AD model rats and found that astrocyte-specific knockout of AT1R significantly ameliorated amyloid β (Aβ)-induced cognitive deficits and synaptotoxicity. Pretreating astrocytes with an AT1R blocker also alleviated Aβ-induced synaptotoxicity in the coculture system of hippocampal neurons and astrocytes. Moreover, AT1R could directly bind to Aβ_1-42 and activate the astrocytic β-arrestin2 pathway in a biased manner, and biased inhibition of the astrocytic AT1R/β-arrestin2 pathway relieved Aβ-induced neurotoxicity. Furthermore, we demonstrated that astrocytic AT1R/β-arrestin2 pathway-mediated synaptotoxicity was associated with the aggregation of autophagosomes, which triggered the disordered degradation of Aβ. Our findings reveal a novel molecular mechanism of astrocytic AT1R in Aβ-induced neurodegeneration and might contribute to establishing new targets for AD prevention and therapy.