Skip to main content

NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression.

Immunity

Authors: Róisín M McManus, Max P Komes, Angelika Griep, Francesco Santarelli, Stephanie Schwartz, Juan Ramón Perea, Johannes C M Schlachetzki, David S Bouvier, Michelle-Amirah Khalil, Mario A Lauterbach, Lea Heinemann, Titus Schlüter, Mehran Shaban Pour, Marta Lovotti, Rainer Stahl, Fraser Duthie, Juan F Rodríguez-Alcázar, Susanne V Schmidt, Jasper Spitzer, Peri Noori, Alberto Maillo, Andreas Boettcher, Brian Herron, John McConville, David Gomez-Cabrero, Jesper Tegnér, Christopher K Glass, Karsten Hiller, Eicke Latz, Michael T Heneka

Activation of the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD) via the release of IL-1β and ASC specks. However, whether NLRP3 is involved in pathways beyond this remained unknown. Here, we found that Aβ deposition in vivo directly triggered NLRP3 activation in APP/PS1 mice, which model many features of AD. Loss of NLRP3 increased glutamine- and glutamate-related metabolism and increased 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 increased clearance of Aβ peptides as well as epigenetic and gene transcription changes. This pathway was conserved between murine and human cells. Critically, we could mimic this effect pharmacologically using NLRP3-specific inhibitors, but only with chronic NLRP3 inhibition. Together, these data demonstrate an additional role for NLRP3, where it can modulate mitochondrial and metabolic function, with important downstream consequences for the progression of AD.

Copyright © 2025 Elsevier Inc. All rights reserved.

PMID: 39904338

Participating cluster members