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TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

Cell, 2017-08, Vol.170 (4), p.649-663.e13 [Peer Reviewed Journal]

2017 Elsevier Inc. ;Copyright © 2017 Elsevier Inc. All rights reserved. ;ISSN: 0092-8674 ;EISSN: 1097-4172 ;DOI: 10.1016/j.cell.2017.07.023 ;PMID: 28802038

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Title:
TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
Author: Ulland, Tyler K. ; Song, Wilbur M. ; Huang, Stanley Ching-Cheng ; Ulrich, Jason D. ; Sergushichev, Alexey ; Beatty, Wandy L. ; Loboda, Alexander A. ; Zhou, Yingyue ; Cairns, Nigel J. ; Kambal, Amal ; Loginicheva, Ekaterina ; Gilfillan, Susan ; Cella, Marina ; Virgin, Herbert W. ; Unanue, Emil R. ; Wang, Yaming ; Artyomov, Maxim N. ; Holtzman, David M. ; Colonna, Marco
Subjects: Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Alzheimer’s disease ; AMP-Activated Protein Kinases - metabolism ; Animals ; Autophagy ; Creatinine - analogs & derivatives ; Creatinine - metabolism ; Disease Models, Animal ; Energy Metabolism ; Humans ; immunity ; Lectins, C-Type - metabolism ; Macrophages - metabolism ; Membrane Glycoproteins - genetics ; Membrane Glycoproteins - metabolism ; metabolism ; Mice ; microglia ; Microglia - metabolism ; Microglia - pathology ; Neurites - metabolism ; Plaque, Amyloid - metabolism ; Receptors, Immunologic - genetics ; Receptors, Immunologic - metabolism ; TOR Serine-Threonine Kinases - metabolism ; TREM2
Is Part Of: Cell, 2017-08, Vol.170 (4), p.649-663.e13
Description: 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. [Display omitted] •TREM2-deficient microglia undergo increased autophagy in an AD mouse model•Microglia in humans with AD-risk-associated TREM2 alleles display marked autophagy•TREM2 deficiency impairs microglial mTOR activation and metabolism•Cyclocreatine improves microglia metabolism and pathology in TREM2-deficient AD mice The Alzheimer’s disease risk factor TREM2 regulates microglial function through modulation of cellular biosynthetic metabolism.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0092-8674
EISSN: 1097-4172
DOI: 10.1016/j.cell.2017.07.023
PMID: 28802038
Source: Cell Press Free Archives
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TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

2017 Elsevier Inc. ;Copyright © 2017 Elsevier Inc. All rights reserved. ;ISSN: 0092-8674 ;EISSN: 1097-4172 ;DOI: 10.1016/j.cell.2017.07.023 ;PMID: 28802038

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