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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, Jörg; Budnik, Bogdan; Lemere, Cynthia; Ikezu, Tsuneya; Heppner, Frank L.; Litvak, Vladimir; Holtzman, David M.; Lassmann, Hans; Weiner, Howard L.; Ochando, Jordi; Haass, Christian ORCID: 0000-0002-4869-1627; Butovsky, Oleg (2017): The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. In: Immunity, Vol. 47, No. 3: pp. 566-581
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Abstract

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 b-amyloid (Ab)-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.