Dihydromyricetin (DHM), a flavonoid found in Ampelopsis grossedentata, reversed spatial learning and memory deficits in SAMP8 accelerated-aging mice after 8 weeks of oral administration by enhancing autophagy-mediated degradation of the NLRP3 inflammasome. In BV2 microglia, DHM at 6.25–25 µg/mL elevated the LC3-II/LC3-I ratio and ULK1 expression while clearing p62, and suppressed LPS/ATP-triggered NLRP3, cleaved caspase-1, IL-1β, and IL-18. Crucially, co-treatment with autophagy inhibitor chloroquine abolished all benefits, confirming mechanism dependence rather than mere correlation.
The NLRP3 inflammasome has emerged as one of the more compelling therapeutic targets in neurodegeneration research over the past decade, with pyroptosis and IL-1β signaling now understood to accelerate amyloid and tau pathology. What makes this work noteworthy is the mechanistic specificity: DHM appears to route NLRP3 protein complexes to LC3- and LAMP1-positive autolysosomes, essentially using the cell's own waste-disposal machinery to extinguish chronic neuroinflammation — a dual hit that most small-molecule NLRP3 inhibitors do not achieve. DHM's concurrent suppression of NF-κB p65 phosphorylation and intracellular ROS adds further mechanistic breadth. Limitations are significant: SAMP8 mice model accelerated senescence rather than classical AD genetics, all data are preclinical, and human pharmacokinetics of oral DHM remain poorly characterized. Still, the chloroquine rescue experiment elevates this above typical natural-compound studies. For researchers tracking autophagy-inflammation crosstalk in aging, this is a solid mechanistic advance, though human translation remains distant.
