Abstract
Astrocytes, the major non-dividing glial cells in the central nervous system, exhibit hyperactivation in Alzheimer's disease (AD), leading to neuroinflammation and cognitive impairments. P2Y1-receptor (P2Y1R) in AD brain has been pointed out some contribution to AD pathogenesis, therefore, this study aims to elucidate how astrocytic P2Y1R affects the progression of AD and explore its potential as a new target for AD therapy. In this study, we performed the two-steps verification to assess P2Y1R inhibition in AD progression: P2Y1R-KO AD mice and AD mice treated with astrocyte-specific P2Y1R gene knockdown by using shRNAs for P2Y1R in adeno-associated virus vector. Histochemistry was conducted for the assessment of amyloid-beta accumulation, neuroinflammation and blood brain barrier function. Expression of inflammatory cytokines was evaluated by qPCR after the separation of astrocytes. Cognitive function was assessed through the Morris water maze, Y maze, and contextual fear conditioning tests. P2Y1R inhibition not only by gene knockout but also by astrocyte-specific knockdown reduced amyloid-beta accumulation, glial neuroinflammation, blood brain barrier dysfunction, and cognitive impairment in an AD mice model. Reduced neuroinflammation by astrocytic P2Y1R silencing in AD was further confirmed by the reduction of IL-6 gene expression after the separation of astrocytes from AD mouse brain, which may relate to the amelioration of blood brain barrier as well as cognitive functions. Our results clearly note that P2Y1R in astrocyte contributes to the progression of AD pathology through the acceleration of neuroinflammation, and one-time gene therapy for silencing astrocytic P2Y1R may offer a new therapeutic target for AD.