TY  - JOUR
AU  - McManus, Róisín M.
AU  - Komes, Max
AU  - Griep, Angelika
AU  - Santarelli, Francesco
AU  - Schwartz, Stephanie
AU  - Perea, Juan Ramon
AU  - Schlachetzki, Johannes C. M.
AU  - Bouvier, David S.
AU  - Khalil, Michelle-Amirah
AU  - Lauterbach, Mario A.
AU  - Heinemann, Lea
AU  - Schlüter, Titus
AU  - Pour, Mehran Shaban
AU  - Lovotti, Marta
AU  - Stahl, Rainer
AU  - Duthie, Fraser
AU  - Rodríguez-Alcázar, Juan F.
AU  - Schmidt, Susanne V.
AU  - Spitzer, Jasper
AU  - Noori, Peri
AU  - Maillo, Alberto
AU  - Boettcher, Andreas
AU  - Herron, Brian
AU  - McConville, John
AU  - Gomez-Cabrero, David
AU  - Tegnér, Jesper
AU  - Glass, Christopher K.
AU  - Hiller, Karsten
AU  - Latz, Eicke
AU  - Heneka, Michael
TI  - NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression
JO  - Immunity
VL  - 58
IS  - 2
SN  - 1074-7613
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-00295
SP  - 326 - 343.e11
PY  - 2025
AB  - 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.
KW  - Alzheimer Disease: metabolism
KW  - Animals
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - Microglia: metabolism
KW  - Microglia: immunology
KW  - Mice
KW  - Humans
KW  - Disease Progression
KW  - Phagocytosis
KW  - Inflammasomes: metabolism
KW  - Mitochondria: metabolism
KW  - Glutamine: metabolism
KW  - Disease Models, Animal
KW  - Amyloid beta-Peptides: metabolism
KW  - Mice, Transgenic
KW  - Mice, Knockout
KW  - Ketoglutaric Acids: metabolism
KW  - Mice, Inbred C57BL
KW  - Alzheimer’s disease (Other)
KW  - NLRP3 (Other)
KW  - amyloid-β (Other)
KW  - dementia (Other)
KW  - glutamine metabolism (Other)
KW  - inflammasome (Other)
KW  - microglia (Other)
KW  - phagocytosis (Other)
KW  - α-ketoglutarate (Other)
KW  - NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
KW  - Inflammasomes (NLM Chemicals)
KW  - Glutamine (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Nlrp3 protein, mouse (NLM Chemicals)
KW  - Ketoglutaric Acids (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39904338
DO  - DOI:10.1016/j.immuni.2025.01.007
UR  - https://pub.dzne.de/record/276473
ER  -