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@ARTICLE{McManus:276473,
      author       = {McManus, Róisín M. and Komes, Max and Griep, Angelika and
                      Santarelli, Francesco and Schwartz, Stephanie and Perea,
                      Juan Ramon and Schlachetzki, Johannes C. M. and Bouvier,
                      David S. and Khalil, Michelle-Amirah and Lauterbach, Mario
                      A. and Heinemann, Lea and Schlüter, Titus and Pour, Mehran
                      Shaban and Lovotti, Marta and Stahl, Rainer and Duthie,
                      Fraser and Rodríguez-Alcázar, Juan F. and Schmidt, Susanne
                      V. and Spitzer, Jasper and Noori, Peri and Maillo, Alberto
                      and Boettcher, Andreas and Herron, Brian and McConville,
                      John and Gomez-Cabrero, David and Tegnér, Jesper and Glass,
                      Christopher K. and Hiller, Karsten and Latz, Eicke and
                      Heneka, Michael},
      title        = {{NLRP}3-mediated glutaminolysis controls microglial
                      phagocytosis to promote {A}lzheimer’s disease progression},
      journal      = {Immunity},
      volume       = {58},
      number       = {2},
      issn         = {1074-7613},
      address      = {[Cambridge, Mass.]},
      publisher    = {Cell Press},
      reportid     = {DZNE-2025-00295},
      pages        = {326 - 343.e11},
      year         = {2025},
      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.},
      keywords     = {Alzheimer Disease: immunology / Alzheimer Disease:
                      metabolism / Animals / NLR Family, Pyrin Domain-Containing 3
                      Protein: metabolism / Microglia: metabolism / Microglia:
                      immunology / Mice / Humans / Disease Progression /
                      Phagocytosis / Inflammasomes: metabolism / Mitochondria:
                      metabolism / Glutamine: metabolism / Disease Models, Animal
                      / Amyloid beta-Peptides: metabolism / Mice, Transgenic /
                      Mice, Knockout / Ketoglutaric Acids: metabolism / Mice,
                      Inbred C57BL / Alzheimer Disease: pathology / NLR Family,
                      Pyrin Domain-Containing 3 Protein: genetics / Alzheimer’s
                      disease (Other) / NLRP3 (Other) / amyloid-β (Other) /
                      dementia (Other) / glutamine metabolism (Other) /
                      inflammasome (Other) / microglia (Other) / phagocytosis
                      (Other) / α-ketoglutarate (Other) / NLR Family, Pyrin
                      Domain-Containing 3 Protein (NLM Chemicals) / Inflammasomes
                      (NLM Chemicals) / Glutamine (NLM Chemicals) / Amyloid
                      beta-Peptides (NLM Chemicals) / Nlrp3 protein, mouse (NLM
                      Chemicals) / Ketoglutaric Acids (NLM Chemicals)},
      cin          = {AG Heneka / AG Latz / AG McManus},
      ddc          = {610},
      cid          = {I:(DE-2719)1011303 / I:(DE-2719)1013024 /
                      I:(DE-2719)1013042},
      pnm          = {353 - Clinical and Health Care Research (POF4-353) / 351 -
                      Brain Function (POF4-351) / 352 - Disease Mechanisms
                      (POF4-352)},
      pid          = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-351 /
                      G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39904338},
      doi          = {10.1016/j.immuni.2025.01.007},
      url          = {https://pub.dzne.de/record/276473},
}