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Neuroinflammation mediated by NLRP-1 inflammasome plays an important role in the pathogenesis of neurodegeneration diseases such as Alzheimer's disease (AD). Chronic glucocorticoids (GCs) exposure has deleterious effect on the structure and function of neurons and was found to be correlated with development and progression of AD. We hypothesize that chronic glucocorticoids may down-regulate the expression of glucocorticoids receptor (GR) and activate NLRP-1 inflammasome in hippocampal neurons, which may promote neuroinflammation and induce neuronal injury. The present results showed that chronic DEX exposure significantly increased LDH release and apoptosis, decreased MAP2 and GR expression in hippocampal neurons. DEX (5 μM) exposure for 3 d significantly increased the expression of NLRP-1, ASC, caspase-1 and IL-1β in the hippocampal neurons and the release of IL-1β and IL-18 in the supernatants. Moreover, DEX (1, 5 μM) treatment for 3 d significantly increased the expression of NF-κB in hippocampal neurons. The GR antagonist, mifepristone (RU486), had protective effects on chronic DEX induced hippocampal neurons injury and NLRP1 inflammasome activation. The results suggest that chronic GCs exposure can decrease GR expression and increase neuroinflammation via NLRP1 inflammasome and promote hippocampal neurons degeneration, which may play an important role in the progression and development of AD.Chronic GCs exposure promotes hippocampal neurons damage.Chronic GCs exposure decreases GR expression in hippocampal neurons.Chronic GCs exposure activates NLRP1 inflammasome in hippocampal neurons.RU486 attenuates chronic GCs induced hippocampal neurons.