TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease

Tyler K. Ulland, Wilbur M. Song, Stanley Ching Cheng Huang, Jason D. Ulrich, Alexey Sergushichev, Wandy L. Beatty, Alexander A. Loboda, Yingyue Zhou, Nigel J. Cairns, Amal Kambal, Ekaterina Loginicheva, Susan Gilfillan, Marina Cella, Herbert W. Virgin, Emil R. Unanue, Yaming Wang, Maxim N. Artyomov, David M. Holtzman, Marco Colonna

Research output: Contribution to journalArticlepeer-review

413 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)649-663.e13
JournalCell
Volume170
Issue number4
DOIs
StatePublished - Aug 10 2017

Keywords

  • Alzheimer's disease
  • TREM2
  • immunity
  • metabolism
  • microglia

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