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Immunity. 2017 Sep 19;47(3):566-581.e9. doi: 10.1016/j.immuni.2017.08.008.

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

Author information

1
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.
2
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
3
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
4
Center for Brain Research, Medical University of Vienna, Vienna, Austria.
5
Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
6
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
7
German Center for Neurodegenerative Diseases, Munich, Germany.
8
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
9
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, USA.
10
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
11
Mass Spectrometry and Proteomics Resource Laboratory, Faculty of Arts and Sciences Division of Science, Harvard University, Cambridge MA, USA.
12
Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, MA, USA.
13
Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany; Cluster of Excellence, NeuroCure, Charitéplatz 1, 10117 Berlin, Germany.
14
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.
15
German Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, Biochemistry, Ludwig-Maximilians-Universität Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany.
16
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.edu.

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 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.

KEYWORDS:

APOE; Alzheimer’s disease; TREM2; amyotrophic lateral sclerosis; microglia; multiple sclerosis; neurodegeneration; transcriptional regulation

PMID:
28930663
PMCID:
PMC5719893
DOI:
10.1016/j.immuni.2017.08.008
[Indexed for MEDLINE]
Free PMC Article

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