2. Academic Validation
  3. NLRP3-mediated glutaminolysis controls microglial phagocytosis to promote Alzheimer's disease progression

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

  • Immunity. 2025 Feb 11;58(2):326-343.e11. doi: 10.1016/j.immuni.2025.01.007.
Róisín M McManus 1,  Max P Komes 1,  Angelika Griep 1,  Francesco Santarelli 1,  Stephanie Schwartz 2,  Juan Ramón Perea 3,  Johannes C M Schlachetzki 4,  David S Bouvier 5,  Michelle-Amirah Khalil 6,  Mario A Lauterbach 1,  Lea Heinemann 7,  Titus Schlüter 1,  Mehran Shaban Pour 1,  Marta Lovotti 2,  Rainer Stahl 2,  Fraser Duthie 2,  Juan F Rodríguez-Alcázar 2,  Susanne V Schmidt 2,  Jasper Spitzer 2,  Peri Noori 8,  Alberto Maillo 9,  Andreas Boettcher 10,  Brian Herron 11,  John McConville 12,  David Gomez-Cabrero 13,  Jesper Tegnér 14,  Christopher K Glass 15,  Karsten Hiller 6,  Eicke Latz 16,  Michael T Heneka 17
Affiliations

Affiliations

  • 1 German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany; Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
  • 2 Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany.
  • 3 German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany; Department of Molecular Neuropathology, Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Madrid 28049, Spain.
  • 4 Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
  • 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367 Belvaux, Luxembourg; Laboratoire National de Santé (LNS), National Center of Pathology (NCP), Dudelange, Luxembourg; Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg.
  • 6 Department of Bioinformatics and Biochemistry, Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany.
  • 7 German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany.
  • 8 Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
  • 9 Translational Bioinformatics Unit, Navarrabiomed, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Navarra, Spain.
  • 10 Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
  • 11 Regional Neuropathology Service, Institute of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Grosvenor Road, Belfast BT12 6BL, Northern Ireland.
  • 12 Ulster Hospital, Dundonald, Northern Ireland.
  • 13 Translational Bioinformatics Unit, Navarrabiomed, Universidad Pública de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Navarra, Spain; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
  • 14 Unit of Computational Medicine, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Biological and Environmental Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia; Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia; Science for Life Laboratory, Tomtebodavagen 23A, 17165, Solna, Sweden.
  • 15 Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
  • 16 German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany; Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Deutsches Rheuma-Forschungszentrum (DRFZ), Charitéplatz 1, 10117 Berlin, Germany.
  • 17 German Center for Neurodegenerative Diseases (DZNE), Venusberg Campus 1/99, 53127 Bonn, Germany; Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4367 Belvaux, Luxembourg; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: michael.heneka@unil.lu.
PMID: 39904338 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.

Keywords

Alzheimer’s disease; NLRP3; amyloid-β; dementia; glutamine metabolism; inflammasome; microglia; phagocytosis; α-ketoglutarate.

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