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

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The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
Immunity ( IF 25.5 ) Pub Date : 2017-09-19 , DOI: 10.1016/j.immuni.2017.08.008
Susanne Krasemann ₁ , Charlotte Madore ₂ , Ron Cialic ₂ , Caroline Baufeld ₂ , Narghes Calcagno ₂ , Rachid El Fatimy ₂ , Lien Beckers ₂ , Elaine O'Loughlin ₂ , Yang Xu ₃ , Zain Fanek ₂ , David J Greco ₂ , Scott T Smith ₂ , George Tweet ₂ , Zachary Humulock ₂ , Tobias Zrzavy ₄ , Patricia Conde-Sanroman ₅ , Mar Gacias ₅ , Zhiping Weng ₆ , Hao Chen ₆ , Emily Tjon ₂ , Fargol Mazaheri ₇ , Kristin Hartmann ₈ , Asaf Madi ₂ , Jason D Ulrich ₉ , Markus Glatzel ₈ , Anna Worthmann ₁₀ , Joerg Heeren ₁₀ , Bogdan Budnik ₁₁ , Cynthia Lemere ₂ , Tsuneya Ikezu ₁₂ , Frank L Heppner ₁₃ , Vladimir Litvak ₃ , David M Holtzman ₉ , Hans Lassmann ₄ , Howard L Weiner ₁₄ , Jordi Ochando ₅ , Christian Haass ₁₅ , Oleg Butovsky ₁₄

Affiliation

Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Center for Brain Research, Medical University of Vienna, Vienna, Austria.
Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
German Center for Neurodegenerative Diseases, Munich, Germany.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, USA.
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Mass Spectrometry and Proteomics Resource Laboratory, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge MA, USA.
Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, MA, USA.
Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
German Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.

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.

中文翻译：

TREM2-APOE途径驱动神经退行性疾病中功能失调的小胶质细胞的转录表型。

小胶质细胞在维持脑稳态中起着关键作用，但在神经退行性疾病中失去稳态功能。我们从肌萎缩性侧索硬化症（ALS），多发性硬化症（MS）和阿尔茨海默氏病（AD）以及神经胶质β-淀粉样蛋白（Aβ）斑块周围的小胶质细胞模型中鉴定了特定的载脂蛋白E（APOE）依赖性分子标记在AD患者的大脑中。凋亡神经元吞噬作用后，APOE途径介导从稳态转移到神经变性小胶质细胞表型。TREM2（在髓样细胞2上表达的触发受体）诱导APOE信号传导，并靶向TREM2-APOE途径在ALS和AD小鼠模型中恢复了小胶质细胞的稳态标志，并防止了神经退行性急性模型中的神经元丢失。APOE介导的神经退行性小胶质细胞失去了致耐受功能。我们的工作确定了TREM2-APOE途径是神经退行性疾病中小胶质细胞功能表型的主要调节剂，并且是可以帮助体内平衡小胶质细胞恢复的新靶标。

更新日期：2017-09-19

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