The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.
Immunity. 2017-09-01; 47(3): 566-581.e9
DOI: 10.1016/j.immuni.2017.08.008
Read on PubMed
1. 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.
Krasemann S(1), Madore C(2), Cialic R(2), Baufeld C(2), Calcagno N(2), El Fatimy
R(2), Beckers L(2), O’Loughlin E(2), Xu Y(3), Fanek Z(2), Greco DJ(2), Smith
ST(2), Tweet G(2), Humulock Z(2), Zrzavy T(4), Conde-Sanroman P(5), Gacias M(5),
Weng Z(6), Chen H(6), Tjon E(2), Mazaheri F(7), Hartmann K(8), Madi A(2), Ulrich
JD(9), Glatzel M(8), Worthmann A(10), Heeren J(10), Budnik B(11), Lemere C(2),
Ikezu T(12), Heppner FL(13), Litvak V(3), Holtzman DM(9), Lassmann H(4), Weiner
HL(14), Ochando J(5), Haass C(15), Butovsky O(16).
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: .
Comment in
Immunity. 2017 Sep 19;47(3):398-400.
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.
Copyright © 2017 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2017.08.008
PMCID: PMC5719893
PMID: 28930663 [Indexed for MEDLINE]