Association between BDNF methylation and expression of the NLRP3 inflammasome in the brain is disrupted in Alzheimer’s disease

Abstract Activation of the NLRP3 inflammasome pathway and dysfunction of brain-derived neurotrophic factor (BDNF) are both implicated in the pathogenesis of Alzheimer’s disease (AD). While in vitro and in vivo models support these mechanisms, there is little research investigating their relationship in human brain tissue, and whether this relationship may be abnormal in the AD brain. Temporal cortex tissue taken post-mortem from AD patients and control subjects was analysed for expression of genes for the NLRP3 pathway (NLRP3, PYCARD, CASP1), the potassium channel THIK1 (KCNK13), and related pro-inflammatory cytokines (IL-1β, IL-18). BDNF mRNA expression and DNA methylation in the BDNF exon IV promoter were determined. Correlations between these BDNF measures and NLRP3-related genes were investigated. A significant relationship between BDNF mRNA expression and mean methylation was observed in control subjects but not in AD. In controls, significant correlations with both BDNF expression and mean BDNF methylation were observed for NLRP3, CASP1 and IL1B. These correlations were lost in the AD group, which also showed a significant correlation of KCNK13 expression with both BDNF measures, not seen in controls. This study indicates that the relationship between BDNF and NLRP3 activation, as measured by NLRP3 inflammasome components and proinflammatory cytokine products, is disrupted in AD. The contrary correlation emerging in AD between BDNF measures and KCNK13 expression, shown to be elevated in AD, indicates the possible relationship of this finding with BDNF dysfunction. These findings enhance our understanding of AD pathophysiology, demonstrating the importance of understanding the neuroinflammatory-neurotrophic balance in neurodegenerative processes.