Ampelopsin alleviates cognitive impairment of SAMP8 mice by inhibiting microglial polarization and NLRP3 degradation via autophagy

Abstract Microglial polarization and NRLP3 inflammasome mediated inflammation response are known to be involved in the pathological procession of AD. Ampelopsin, a natural flavonoid compound from Chinese herb Ampelopsis grossedentata , has been reported to have neuroprotective functions. However, there have been no reports on whether DHM suppresses microglial polarization and NLRP3-Caspase-1 inflammasome via autophagy pathway in an Alzheimer’s disease model. We aimed to study the effects of ampelopsin on M1/M2 polarization and the mechanism to regulate anti-inflammation both in vivo and vitro models. BV2 cells were treated with LPS in the presence or absence of DHM, and SAMP8 mice were orally administered 100 or 200 mg/kg/day of DHM for 8 weeks. Our results showed that ampelopsin significantly mitigated cognitive impairment and AD-like pathological proteins（BACE1 and APP）levels in AD mice. Treatment with different dose of ampelopsin efficiently suppressed NLRP3-Caspase-1 inflammasome activation, IL-1β and IL-18 production as well as microglia activation in the hippocampus of SAMP8 mice. Mechanistically, DHM promoted the transition from M1 to M2 microglia by up-regulating SIRT1 signaling. Transmission electron microscopy results further confirmed that DHM reversed impaired autophagy in AD mice. However, CQ, as an autophagy inhibitor, not only blocked the above protective effects of DHM in vivo, but also exacerbated those pathological changes. Our findings reveals activation of autophagic induced by DHM promote M2 polarization, NLRP3 inflammasome degradation, inhibiting inflammatory response, in turn, improving cognitive function in SAMP8 mice.