NLRP3-mediated glutaminolysis regulates microglia in Alzheimer’s disease [ChIP-Seq]

Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer’s disease (AD), via the characterised release of IL-1β and ASC specks. However, whether NLRP3 was involved in pathways beyond this remained unknown. Here we show that loss of NLRP3 influences glutamine/glutamate-related metabolism and increases expression of microglial Slc1a3, which was associated with enhanced mitochondrial and metabolic activity. The generation of α-ketoglutarate during this process impacted cellular function including more significant clearance of Aβ peptides, epigenetic and gene transcription changes. This pathway is conserved between murine and human cells. Critically, we can mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrates a new role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.