Dihydro-resveratrol ameliorates NLRP3 inflammasome-mediated neuroinflammation via Bnip3-dependent mitophagy in Alzheimer's disease

Dihydro-resveratrol (DHR), a polyphenol derivative, that has been demonstrated to suppress inflammation-mediated injury. However, it is still unknown whether it has anti-neuroinflammatory and neuroprotective effects, and a therapeutic action in Alzheimer's disease (AD). The anti-inflammatory and anti-Alzheimer's disease actions of dihydro-resveratrol were investigated using lipopolysaccharide (LPS) and AD mice models, and primary microglial cells. The changes in behaviour in mice were detected by the Morris water maze test and open-field test. Flow cytometry assay, western blotting, immunofluorescence assays and co-immunoprecipitation were used to investigate the changes in the NLRP3 inflammasome activation and mitophagy. In this study, in vivo observations indicated that the administration of dihydro-resveratrol (DHR) dramatically restored spatial learning, memory ability, autophagy and mitophagy, attenuated NLRP3 inflammasome activation, neuroinflammation and amyloid precursor protein pathology in LPS mice and AD mice. In addition, the inhibition of autophagy and mitophagy, or the activation of NLRP3 in vivo greatly abolished DHR-generated therapeutic efficacy on neuroinflammation, amyloid precursor protein pathology and cognitive loss. Further examination indicated that the application of DHR after the LPS and ATP exposure significantly inhibited the NLRP3 inflammasome activation, neuroinflammation and enhanced autophagic and mitophagic activation in microglia. Additionally, in vitro results show that DHR protects microglial cells against LPS and ATP-induced cytotoxicity by inhibiting NLRP3 inflammasome through activating Bnip3-dependent mitophagy and ULK phosphorylation. In summary, these findings suggest that dihydro-resveratrol (DHR) possesses potent anti-neuroinflammatory property and can act as a potential therapeutic agent for the treatment of AD.