NO(2) inhalation promotes Alzheimer’s disease-like progression: cyclooxygenase-2-derived prostaglandin E(2) modulation and monoacylglycerol lipase inhibition-targeted medication

Air pollution has been reported to be associated with increased risks of cognitive impairment and neurodegenerative diseases. Because NO(2) is a typical primary air pollutant and an important contributor to secondary aerosols, NO(2)-induced neuronal functional abnormalities have attracted greater attention, but the available experimental evidence, modulating mechanisms, and targeting medications remain ambiguous. In this study, we exposed C57BL/6J and APP/PS1 mice to dynamic NO(2) inhalation and found for the first time that NO(2) inhalation caused deterioration of spatial learning and memory, aggravated amyloid β(42) (Aβ(42)) accumulation, and promoted pathological abnormalities and cognitive defects related to Alzheimer’s disease (AD). The microarray and bioinformation data showed that the cyclooxygenase-2 (COX-2)-mediated arachidonic acid (AA) metabolism of prostaglandin E(2) (PGE(2)) played a key role in modulating this aggravation. Furthermore, increasing endocannabinoid 2-arachidonoylglycerol (2-AG) by inhibiting monoacylglycerol lipase (MAGL) prevented PGE(2) production, neuroinflammation-associated Aβ(42) accumulation, and neurodegeneration, indicating a therapeutic target for relieving cognitive impairment caused by NO(2) exposure.