Journal Article

DZNE-2025-00295

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer’s disease progression

McManus, R. M. (First author)DZNE* ; Komes, M.DZNE* ; Griep, A.DZNE* ; Santarelli, F.DZNE* ; Schwartz, S. ; Perea, J. R.DZNE* ; Schlachetzki, J. C. M. ; Bouvier, D. S. ; Khalil, M.-A. ; Lauterbach, M. A.DZNE* ; Heinemann, L.DZNE* ; Schlüter, T.DZNE* ; Pour, M. S.DZNE* ; Lovotti, M. ; Stahl, R. ; Duthie, F. ; Rodríguez-Alcázar, J. F. ; Schmidt, S. V. ; Spitzer, J. ; Noori, P. ; Maillo, A. ; Boettcher, A. ; Herron, B. ; McConville, J. ; Gomez-Cabrero, D. ; Tegnér, J. ; Glass, C. K. ; Hiller, K. ; Latz, E. (Last author)DZNE* ; Heneka, M. (Last author)DZNE*

2025
Cell Press [Cambridge, Mass.]

This record in other databases:    

Please use a persistent id in citations: doi:10.1016/j.immuni.2025.01.007

Abstract: 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.

Keyword(s): Alzheimer Disease: metabolism (MeSH) ; Animals (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: immunology (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Disease Progression (MeSH) ; Phagocytosis (MeSH) ; Inflammasomes: metabolism (MeSH) ; Mitochondria: metabolism (MeSH) ; Glutamine: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Mice, Transgenic (MeSH) ; Mice, Knockout (MeSH) ; Ketoglutaric Acids: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Alzheimer’s disease ; NLRP3 ; amyloid-β ; dementia ; glutamine metabolism ; inflammasome ; microglia ; phagocytosis ; α-ketoglutarate ; NLR Family, Pyrin Domain-Containing 3 Protein ; Inflammasomes ; Glutamine ; Amyloid beta-Peptides ; Nlrp3 protein, mouse ; Ketoglutaric Acids

---

Contributing Institute(s):

1. Neuroinflammation, Biomarker (AG Heneka)
2. Innate Immunity in Neurodegeneration (AG Latz)
3. Translational Neuroimmunology (AG McManus)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 351 - Brain Function (POF4-351) (POF4-351)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---