TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease

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. Her...

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Published in:	Cell 2017-08, Vol.170 (4), p.649-663.e13
Main Authors:	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
Format:	Article
Language:	eng
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
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Summary:	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.
ISSN:	0092-8674 1097-4172