Neuroprotective Effects of Glucosamine in Huntington's Disease Through NLRP3 Inflammasome Inhibition

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. It typically manifests as a triad of progressive psychiatric, cognitive, and motor symptoms. The resulting mutant HTT (mHTT) protein disrupts cellular homeostasis and promotes neuroinflammation. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is a key mediator of neuroinflammatory responses, activating caspase-1 and promoting the release of interleukin (IL)-1β and IL-18. In this study, we investigated the neuroprotective potential of glucosamine (GlcN) in HD. Our results demonstrate that GlcN effectively attenuates lipopolysaccharide (LPS)/ATP-induced NLRP3 inflammasome activation in BV2 microglia, leading to a significant reduction in IL-1β and IL-18 secretion. Mechanistically, GlcN suppresses microglial activation by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, thereby reducing nuclear factor-κB (NF-κB) activation. In the R6/2 transgenic mouse model of HD, oral administration of GlcN significantly enhanced neuronal survival, reduced mHTT aggregation, suppressed NLRP3 inflammasome activation, and attenuated astrocytic and microglial activation. Furthermore, GlcN improved motor performance and extended the lifespan of R6/2 mice. These findings suggest that GlcN confers neuroprotection in HD by attenuating neuroinflammation through inhibition of the NLRP3 inflammasome. Our study shows that GlcN is an effective treatment candidate for HD by targeting neuroinflammatory pathways, particularly through inhibition of the NLRP3 inflammasome, thereby presenting a promising strategy to slow disease progression.