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000276473 005__ 20250213091511.0
000276473 0247_ $$2doi$$a10.1016/j.immuni.2025.01.007
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000276473 041__ $$aEnglish
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000276473 1001_ $$0P:(DE-2719)2811671$$aMcManus, Róisín M.$$b0$$eFirst author
000276473 245__ $$aNLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression
000276473 260__ $$a[Cambridge, Mass.]$$bCell Press$$c2025
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000276473 520__ $$aActivation 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.
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000276473 650_7 $$2Other$$aAlzheimer’s disease
000276473 650_7 $$2Other$$aNLRP3
000276473 650_7 $$2Other$$aamyloid-β
000276473 650_7 $$2Other$$adementia
000276473 650_7 $$2Other$$aglutamine metabolism
000276473 650_7 $$2Other$$ainflammasome
000276473 650_7 $$2Other$$amicroglia
000276473 650_7 $$2Other$$aphagocytosis
000276473 650_7 $$2Other$$aα-ketoglutarate
000276473 650_7 $$2NLM Chemicals$$aNLR Family, Pyrin Domain-Containing 3 Protein
000276473 650_7 $$2NLM Chemicals$$aInflammasomes
000276473 650_7 $$00RH81L854J$$2NLM Chemicals$$aGlutamine
000276473 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000276473 650_7 $$2NLM Chemicals$$aNlrp3 protein, mouse
000276473 650_7 $$2NLM Chemicals$$aKetoglutaric Acids
000276473 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000276473 650_2 $$2MeSH$$aAnimals
000276473 650_2 $$2MeSH$$aNLR Family, Pyrin Domain-Containing 3 Protein: metabolism
000276473 650_2 $$2MeSH$$aMicroglia: metabolism
000276473 650_2 $$2MeSH$$aMicroglia: immunology
000276473 650_2 $$2MeSH$$aMice
000276473 650_2 $$2MeSH$$aHumans
000276473 650_2 $$2MeSH$$aDisease Progression
000276473 650_2 $$2MeSH$$aPhagocytosis
000276473 650_2 $$2MeSH$$aInflammasomes: metabolism
000276473 650_2 $$2MeSH$$aMitochondria: metabolism
000276473 650_2 $$2MeSH$$aGlutamine: metabolism
000276473 650_2 $$2MeSH$$aDisease Models, Animal
000276473 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000276473 650_2 $$2MeSH$$aMice, Transgenic
000276473 650_2 $$2MeSH$$aMice, Knockout
000276473 650_2 $$2MeSH$$aKetoglutaric Acids: metabolism
000276473 650_2 $$2MeSH$$aMice, Inbred C57BL
000276473 7001_ $$0P:(DE-2719)9001384$$aKomes, Max$$b1
000276473 7001_ $$0P:(DE-2719)2811029$$aGriep, Angelika$$b2
000276473 7001_ $$0P:(DE-2719)2810567$$aSantarelli, Francesco$$b3
000276473 7001_ $$0P:(DE-HGF)0$$aSchwartz, Stephanie$$b4
000276473 7001_ $$0P:(DE-2719)9002194$$aPerea, Juan Ramon$$b5
000276473 7001_ $$aSchlachetzki, Johannes C. M.$$b6
000276473 7001_ $$aBouvier, David S.$$b7
000276473 7001_ $$aKhalil, Michelle-Amirah$$b8
000276473 7001_ $$0P:(DE-HGF)0$$aLauterbach, Mario A.$$b9
000276473 7001_ $$0P:(DE-HGF)0$$aHeinemann, Lea$$b10
000276473 7001_ $$0P:(DE-HGF)0$$aSchlüter, Titus$$b11
000276473 7001_ $$0P:(DE-HGF)0$$aPour, Mehran Shaban$$b12
000276473 7001_ $$aLovotti, Marta$$b13
000276473 7001_ $$aStahl, Rainer$$b14
000276473 7001_ $$aDuthie, Fraser$$b15
000276473 7001_ $$aRodríguez-Alcázar, Juan F.$$b16
000276473 7001_ $$aSchmidt, Susanne V.$$b17
000276473 7001_ $$aSpitzer, Jasper$$b18
000276473 7001_ $$aNoori, Peri$$b19
000276473 7001_ $$aMaillo, Alberto$$b20
000276473 7001_ $$aBoettcher, Andreas$$b21
000276473 7001_ $$aHerron, Brian$$b22
000276473 7001_ $$aMcConville, John$$b23
000276473 7001_ $$aGomez-Cabrero, David$$b24
000276473 7001_ $$aTegnér, Jesper$$b25
000276473 7001_ $$aGlass, Christopher K.$$b26
000276473 7001_ $$aHiller, Karsten$$b27
000276473 7001_ $$0P:(DE-2719)2000062$$aLatz, Eicke$$b28$$eLast author
000276473 7001_ $$0P:(DE-2719)2000008$$aHeneka, Michael$$b29$$eLast author
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