Your browser doesn't support javascript.
loading
The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
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.
Affiliation
  • Krasemann S; 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.
  • Madore C; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Cialic R; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Baufeld C; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Calcagno N; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • El Fatimy R; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Beckers L; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • O'Loughlin E; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Xu Y; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
  • Fanek Z; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Greco DJ; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Smith ST; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Tweet G; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Humulock Z; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Zrzavy T; Center for Brain Research, Medical University of Vienna, Vienna, Austria.
  • Conde-Sanroman P; Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
  • Gacias M; Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
  • Weng Z; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
  • Chen H; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
  • Tjon E; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Mazaheri F; German Center for Neurodegenerative Diseases, Munich, Germany.
  • Hartmann K; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Madi A; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Ulrich JD; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, USA.
  • Glatzel M; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Worthmann A; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Heeren J; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Budnik B; Mass Spectrometry and Proteomics Resource Laboratory, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge MA, USA.
  • Lemere C; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Ikezu T; Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, MA, USA.
  • Heppner FL; Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
  • Litvak V; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
  • Holtzman DM; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, USA.
  • Lassmann H; Center for Brain Research, Medical University of Vienna, Vienna, Austria.
  • Weiner HL; 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.
  • Ochando J; Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
  • Haass C; German Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
  • Butovsky O; 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. Electronic address: obutovsky@rics.bwh.harvard
Immunity ; 47(3): 566-581.e9, 2017 09 19.
Article in En | MEDLINE | ID: mdl-28930663
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 ß-amyloid (Aß)-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.
Subject(s)
Key words
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Apolipoproteins E / Membrane Glycoproteins / Receptors, Immunologic / Signal Transduction / Microglia / Neurodegenerative Diseases / Transcriptome Type of study: Prognostic_studies Language: En Journal: Immunity Journal subject: ALERGIA E IMUNOLOGIA Year: 2017 Type: Article Affiliation country: Germany
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Apolipoproteins E / Membrane Glycoproteins / Receptors, Immunologic / Signal Transduction / Microglia / Neurodegenerative Diseases / Transcriptome Type of study: Prognostic_studies Language: En Journal: Immunity Journal subject: ALERGIA E IMUNOLOGIA Year: 2017 Type: Article Affiliation country: Germany