The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (...

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Veröffentlicht in:	Immunity (Cambridge, Mass.) Jg. 47; H. 3; S. 566
Hauptverfasser:	Krasemann, Susanne, Madore, Charlotte, Cialic, Ron, Baufeld, Caroline, Calcagno, Narghes, El Fatimy, Rachid, Beckers, Lien, O'Loughlin, Elaine, Xu, Yang, Fanek, Zain, Greco, David J, Smith, Scott T, Tweet, George, Humulock, Zachary, Zrzavy, Tobias, Conde-Sanroman, Patricia, Gacias, Mar, Weng, Zhiping, Chen, Hao, Tjon, Emily, Mazaheri, Fargol, Hartmann, Kristin, Madi, Asaf, Ulrich, Jason D, Glatzel, Markus, Worthmann, Anna, Heeren, Joerg, Budnik, Bogdan, Lemere, Cynthia, Ikezu, Tsuneya, Heppner, Frank L, Litvak, Vladimir, Holtzman, David M, Lassmann, Hans, Weiner, Howard L, Ochando, Jordi, Haass, Christian, Butovsky, Oleg
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 19.09.2017
Schlagworte:	Alzheimer Disease - genetics Alzheimer Disease - metabolism Alzheimer Disease - pathology Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - metabolism Animals Apolipoproteins E - deficiency Apolipoproteins E - genetics Apolipoproteins E - metabolism Apoptosis - genetics Apoptosis - immunology Cerebral Cortex - metabolism Cerebral Cortex - pathology Cluster Analysis Disease Models, Animal Encephalomyelitis, Autoimmune, Experimental Female Gene Expression Profiling Gene Expression Regulation Gene Targeting Humans Immune Tolerance Membrane Glycoproteins - metabolism Mice Mice, Knockout Mice, Transgenic Microglia - immunology Microglia - metabolism Monocytes - immunology Monocytes - metabolism Neurodegenerative Diseases - genetics Neurodegenerative Diseases - immunology Neurodegenerative Diseases - metabolism Neurons - metabolism Phagocytosis - genetics Phagocytosis - immunology Phenotype Plaque, Amyloid - metabolism Plaque, Amyloid - pathology Receptors, Immunologic - metabolism Signal Transduction Superoxide Dismutase-1 - genetics Superoxide Dismutase-1 - metabolism Transcriptome Transforming Growth Factor beta - metabolism Alzheimer’s disease multiple sclerosis transcriptional regulation neurodegeneration TREM2 APOE amyotrophic lateral sclerosis microglia
ISSN:	1097-4180, 1097-4180
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Zusammenfassung:	Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4180 1097-4180
DOI:	10.1016/j.immuni.2017.08.008