TY - JOUR
T1 - TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease
AU - Ulland, Tyler K.
AU - Song, Wilbur M.
AU - Huang, Stanley Ching Cheng
AU - Ulrich, Jason D.
AU - Sergushichev, Alexey
AU - Beatty, Wandy L.
AU - Loboda, Alexander A.
AU - Zhou, Yingyue
AU - Cairns, Nigel J.
AU - Kambal, Amal
AU - Loginicheva, Ekaterina
AU - Gilfillan, Susan
AU - Cella, Marina
AU - Virgin, Herbert W.
AU - Unanue, Emil R.
AU - Wang, Yaming
AU - Artyomov, Maxim N.
AU - Holtzman, David M.
AU - Colonna, Marco
N1 - Funding Information:
We would like to thank Dr. Edward Driggers at General Metabolomics for providing metabolite analysis services. We also would like to thank Drs. Edward J. Pearce and David E. Sanin at the Max Planck Institute of Immunobiology and Epigenetics for discussions and experimental assistance. Finally, we would like to thank Dr. Robert E. Schmidt for assistance in interpreting TEM images. Confocal imaging was performed at the Washington University Center for Cellular Imaging. This work was funded by the NIH (RF1AG05148501 to M.Co., 5T32CA009547-30 to T.K.U., DK058177 to E.R.U., and P01 AG03991 and P01 AG026276 to D.M.H.), Knight ADRC (P50 AG0568 1 to M.Co.), the Cure Alzheimer's Fund (to M.Co.), the National Multiple Sclerosis Society (RG4687A1/1 to M.Ce.), and the Government of Russian Federation (074-U01 to A.S. and A.A.L.). Y.W. is currently employed by Eli Lilly and Company.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/8/10
Y1 - 2017/8/10
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - TREM2
KW - immunity
KW - metabolism
KW - microglia
UR - http://www.scopus.com/inward/record.url?scp=85027528978&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2017.07.023
DO - 10.1016/j.cell.2017.07.023
M3 - Article
C2 - 28802038
AN - SCOPUS:85027528978
SN - 0092-8674
VL - 170
SP - 649-663.e13
JO - Cell
JF - Cell
IS - 4
ER -