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TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.

Cell | Aug 10, 2017

Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.

Pubmed ID: 28802038 RIS Download

Mesh terms: AMP-Activated Protein Kinases | Alzheimer Disease | Animals | Autophagy | Creatinine | Disease Models, Animal | Energy Metabolism | Humans | Lectins, C-Type | Macrophages | Membrane Glycoproteins | Mice | Microglia | Neurites | Plaque, Amyloid | Receptors, Immunologic | TOR Serine-Threonine Kinases

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK058177
  • Agency: NIA NIH HHS, Id: P01 AG003991
  • Agency: NIA NIH HHS, Id: P50 AG005681
  • Agency: NIA NIH HHS, Id: P01 AG026276
  • Agency: NIAID NIH HHS, Id: R01 AI114551
  • Agency: NCI NIH HHS, Id: T32 CA009547
  • Agency: NIA NIH HHS, Id: RF1 AG051485

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