Inhibition of NLRP3 through MCC950 reduces neuroinflammation and increases BDNF signaling in a mouse model of Huntington’s Disease.

Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the HTT gene and characterized by progressive cognitive and motor decline. Mutant huntingtin (mHTT) forms intranuclear inclusions (NIIs), promotes microglial activation, and impairs cortico-striatal Brain-Derived Neurotrophic Factor (BDNF) transport. BDNF is crucial for the survival of striatal Medium Spiny Neurons (MSNs), and its depletion triggers progressive neuronal loss, driving chronic neuroinflammation. Recently, NOD- LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of neuroinflammation and pyroptosis in HD. However, effective in vivo strategies to counteract its activation remain to be fully explored. Therefore, we hypothesized that the selective inhibition of NLRP3 by MCC950, by preventing its assembly, could exert neuroprotective effects in R6/2 mice. To test this, WT and pre-symptomatic R6/2 mice were intraperitoneally injected with either vehicle (0.9% saline solution) or MCC950 (10 mg/kg daily) from 4 weeks of age until their natural death. Motor performance was assessed weekly using Open Field and Rotarod tests, while body weight and survival rate were also monitored. Following sacrifice, immunofluorescence was performed to evaluate NLRP3 inhibition, microglial activation and BDNF modulation. Additionally, Golgi-Cox staining was used to analyze the effects of MCC950 on MSNs’ dendritic spine density in the dorsal striatum. Notably, R6/2 mice treated with MCC950 showed a significant extension in lifespan compared to R6/2 control littermates. Furthermore, MCC950 reduced NLRP3 inflammasome and microglial activation, restored BDNF levels, and preserved MSNs dendritic spine density. Behavioral analyses are currently ongoing. These results demonstrate that MCC950 mitigates NLRP3-mediated neuroinflammation and exerts neurotrophic effects on R6/2 mouse model, suggesting it as a promising therapeutic candidate for HD.