Functional significance of NLRP3 polymorphisms in mild cognitive impairment

Nucleotide-binding domain and leucine-rich repeat (LRR)-containing family protein 3 (NLRP3) inflammasome is an essential component of the innate immune system and regulates inflammation. NLRP3 inflammasome has been widely studied in the pathogenesis of mild cognitive impairments (MCI) and Alzheimer’s Disease (AD). Single nucleotide polymorphisms (SNPs) of NLRP3 gene are associated with various diseases, however the association between NLRP3 SNPs and downstream pathway is unclear. 12 tag SNPs and 2 previously reported SNPs were genotyped in 233 healthy controls (HC) and 332 MCI older adults. NLRP3 and other inflammation-related genes expression were quantified in peripheral blood mononuclear cells (PBMC) from the older adults by quantitative PCR (qPCR). Functional studies of selected mutations were performed by luciferase assay. The older adults were followed up for 2 years to investigate the relationship between NLRP3 SNPs and risk of cognitive decline. Our study showed rs10754558 and rs7525979 were associated with an increased risk of MCI. The T allele of rs12564791 was associated with higher gene expression level of NLRP3, interleukin-18 (IL-18), PYCARD, and CASP1. rs12048215, rs10754555, and rs7525979 were associated with cognitive decline as shown by the reduction of Montreal Cognitive Assessment (MoCA) score. Functional studies showed that both rs10754558 and rs10754555 G to C mutation affected transcriptional activity. rs10754558 G to C mutation also disturbed the interaction between NLRP3 3’UTR and miR-425-5p. Plasma miR-425-5p expression was negatively correlated with MoCA score. Our study suggested that genetic variations of NLRP3 could affect inflammatory gene expression, transcriptional activity and interaction between gene and miRNA, and therefore were associated with the risk of MCI and cognitive decline. Plasma miR-425-5p has the potential to be a biomarker for cognitive decline.