MISSING LINK BETWEEN NLRP3 MEDIATED NEUROINFLAMMATION AND MICRO RNA IN ALZHEIMER'S DISEASE

Abstract

NOD-LRR and pyrin domain containing protein 3 (NLRP3) is abundantly expressed in macrophages and is involved in neuroinflammation in the brain. Together with an adaptor protein called apoptosis associated speck like protein and pro-caspase-1, it forms an inflammasome complex. Inflammasome complex produces IL-1β and IL-18 and can trigger inflammation. NLRP3 inflammasome mediated chronic neuroinflammation was found to be a major factor in several neurodegenerative diseases (NDDs) like Alzheimer’s disease (AD). Several reports elucidated the role of inflammasome in AD such as Aβ aggregation and Tau hyper-phosphorylation were found to be elevated by NLRP3 mediated neuroinflammation. Taking into account of the functional importance of NLRP3 inflammasome, it is needed to identify the regulatory mechanisms which control the expression of the NLRP3 gene. One such regulatory mechanism is MicroRNA (miRNA) mediated regulation where a miRNA can target the untranslated regions (UTRs) of the target gene thus reducing the expression of that gene. In this study, different step by step computational analysis were performed which included healthy brain tissue expression, presence of polymorphism at 3’ UTR of NLRP3, ability to regulate the transcription factors of NLRP3, and microarray analysis of dysregulated miRNAs in AD patients. After that a thorough insilico validation was performed which involved pathway analysis, miRNA sponge analysis, and mRNA-miRNA binding site accessibility prediction by evaluating RNA secondary structure. Finally, ten novel miRNAs (hsa-17-5p, hsa 20b-5p, hsa-27a-3p, hsa-186-5p, hsa-30d-5p, hsa-30a-5p, hsa-30e-5p, hsa-338-3p, hsa-223-3p, and hsa-548a-3p) were reported having the most potentiality to regulate the expression of NLRP3 in AD.