The neuroprotection of progesterone against Aβ-induced NLRP3-Caspase-1 inflammasome activation via enhancing autophagy in astrocytes.

Neuroinflammation and autophagy dysfunction are known to be involved in the pathological procession of Alzheimer's disease (AD). Progesterone (PG), neuroactive steroids, exerts a characteristic neuroprotective function in improving AD syndrome. The NOD-like receptor pyrin 3 (NLRP3)-Caspase-1 inflammasome has specific relevance to AD pathological procession. However, the exact role of PG in regulating NLRP3-Caspase-1 inflammasome remains to be elucidated. We demonstrated Aβ up-regulated IL-1β expression in astrocytes by activating NLRP3-Caspase-1 inflammasome. However, pharmacological activation of autophagy by Rapamycin (RAPA) efficiently suppressed Aβ-, lipopolysaccharides (LPS)-induced IL-1β expression via regulating NLRP3-Caspase-1 inflammasome in astrocytes. Remarkably, PG significantly inhibited Aβ-induced NLRP3-Caspase-1 inflammasome activation. Autophagy inhibitor 3-MA blocked the protective effects of PG in mediating NLRP3 inflammasome and IL-1β processing. Taken together, our observations suggest that autophagy-lysosome pathway is one specific molecular mechanism in regulating Aβ-induced NLRP3-Caspase-1 inflammasome activation in astrocytes, particularly uncover the potential neuroprotection of PG in regulating upstream signaling leading to the sequence events of neuroinflammation. That neuroprotective mechanism of PG in regulating NLRP3-Caspase-1 inflammasome can be a potential therapeutic target for ameliorating the pathological procession of AD.