Astrocytic GluN2A alleviates sleep deprivation-induced elevation of Aβ through regulating neprilysin and AQP4 via the calcineurin/NFAT pathway.

Abstract

Sleep disorders can increase amyloid beta (Aβ) burden in the brain and are linked to Alzheimer's disease (AD) risk. The precise mechanism by which sleep disturbances elevate Aβ levels is unclear. Our previous study has demonstrated that knocking down encoding gene Grin2a of astrocytic N-methyl-D-aspartate (NMDA) receptors GluN2A subunit could aggravate sleep deprivation (SD)-induced elevation of Aβ, indicating a protective role of astrocytic GluN2A in SD; but the underlying mechanism needs to be further elucidated. In our present study, using rat models of SD combined with specific astrocytic Grin2a knockdown or overexpression in the hippocampus, and a cell model of primary cultured hippocampal astrocytes, we reveal a novel mechanism that astrocytic GluN2A alleviates SD-induced increases in Aβ. We demonstrated that astrocytic GluN2A mainly affected Aβ degradation and clearance through regulating degradation enzyme neprilysin and Aquaporin-4 (AQP4), via the calcineurin/NFAT pathway. Our study provides supportive evidence for the novel role and mechanism of astrocytic GluN2A in Aβ elimination, which would contribute to the discovery of new therapeutic strategies for Aβ-related diseases such as AD.