PMID- 28930663
OWN - NLM
STAT- MEDLINE
DCOM- 20171018
LR  - 20191220
IS  - 1097-4180 (Electronic)
IS  - 1074-7613 (Print)
IS  - 1074-7613 (Linking)
VI  - 47
IP  - 3
DP  - 2017 Sep 19
TI  - The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional 
      Microglia in Neurodegenerative Diseases.
PG  - 566-581.e9
LID - S1074-7613(17)30366-7 [pii]
LID - 10.1016/j.immuni.2017.08.008 [doi]
AB  - 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 beta-amyloid (Abeta)-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.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Krasemann, Susanne
AU  - Krasemann S
AD  - 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.
FAU - Madore, Charlotte
AU  - Madore C
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Cialic, Ron
AU  - Cialic R
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Baufeld, Caroline
AU  - Baufeld C
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Calcagno, Narghes
AU  - Calcagno N
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - El Fatimy, Rachid
AU  - El Fatimy R
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Beckers, Lien
AU  - Beckers L
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - O'Loughlin, Elaine
AU  - O'Loughlin E
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Xu, Yang
AU  - Xu Y
AD  - Department of Microbiology and Physiological Systems, University of Massachusetts 
      Medical School, Worcester, MA, USA.
FAU - Fanek, Zain
AU  - Fanek Z
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Greco, David J
AU  - Greco DJ
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Smith, Scott T
AU  - Smith ST
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Tweet, George
AU  - Tweet G
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Humulock, Zachary
AU  - Humulock Z
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Zrzavy, Tobias
AU  - Zrzavy T
AD  - Center for Brain Research, Medical University of Vienna, Vienna, Austria.
FAU - Conde-Sanroman, Patricia
AU  - Conde-Sanroman P
AD  - Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
FAU - Gacias, Mar
AU  - Gacias M
AD  - Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
FAU - Weng, Zhiping
AU  - Weng Z
AD  - Department of Biochemistry and Molecular Pharmacology, University of 
      Massachusetts Medical School, Worcester, MA, USA.
FAU - Chen, Hao
AU  - Chen H
AD  - Department of Biochemistry and Molecular Pharmacology, University of 
      Massachusetts Medical School, Worcester, MA, USA.
FAU - Tjon, Emily
AU  - Tjon E
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Mazaheri, Fargol
AU  - Mazaheri F
AD  - German Center for Neurodegenerative Diseases, Munich, Germany.
FAU - Hartmann, Kristin
AU  - Hartmann K
AD  - Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 
      Hamburg, Germany.
FAU - Madi, Asaf
AU  - Madi A
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Ulrich, Jason D
AU  - Ulrich JD
AD  - Department of Neurology, Hope Center for Neurological Disorders, Knight 
      Alzheimer's Disease Research Center, Washington University School of Medicine, 
      St. Louis, USA.
FAU - Glatzel, Markus
AU  - Glatzel M
AD  - Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 
      Hamburg, Germany.
FAU - Worthmann, Anna
AU  - Worthmann A
AD  - Department of Biochemistry and Molecular Cell Biology, University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Heeren, Joerg
AU  - Heeren J
AD  - Department of Biochemistry and Molecular Cell Biology, University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Budnik, Bogdan
AU  - Budnik B
AD  - Mass Spectrometry and Proteomics Resource Laboratory, Faculty of Arts and 
      Sciences Division of Science, Harvard University, Cambridge MA, USA.
FAU - Lemere, Cynthia
AU  - Lemere C
AD  - Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and 
      Women's Hospital, Harvard Medical School, Boston, MA, USA.
FAU - Ikezu, Tsuneya
AU  - Ikezu T
AD  - Department of Pharmacology and Experimental Therapeutics and Department of 
      Neurology, Boston University School of Medicine, MA, USA.
FAU - Heppner, Frank L
AU  - Heppner FL
AD  - Department of Neuropathology, Charite-Universitatsmedizin Berlin, Berlin, 
      Germany; Cluster of Excellence, NeuroCure, Chariteplatz 1, 10117 Berlin, Germany.
FAU - Litvak, Vladimir
AU  - Litvak V
AD  - Department of Microbiology and Physiological Systems, University of Massachusetts 
      Medical School, Worcester, MA, USA.
FAU - Holtzman, David M
AU  - Holtzman DM
AD  - Department of Neurology, Hope Center for Neurological Disorders, Knight 
      Alzheimer's Disease Research Center, Washington University School of Medicine, 
      St. Louis, USA.
FAU - Lassmann, Hans
AU  - Lassmann H
AD  - Center for Brain Research, Medical University of Vienna, Vienna, Austria.
FAU - Weiner, Howard L
AU  - Weiner HL
AD  - 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.
FAU - Ochando, Jordi
AU  - Ochando J
AD  - Department of Medicine, Icahn School of Medicine at Mount Sinai, NY, USA.
FAU - Haass, Christian
AU  - Haass C
AD  - German Center for Neurodegenerative Diseases, Munich, Germany; Biomedical Center, 
      Biochemistry, Ludwig-Maximilians-Universitat Munich, Munich, Germany; Munich 
      Cluster for Systems Neurology, Munich, Germany.
FAU - Butovsky, Oleg
AU  - Butovsky O
AD  - 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.
LA  - eng
GR  - RF1 AG054199/AG/NIA NIH HHS/United States
GR  - R01 AG040092/AG/NIA NIH HHS/United States
GR  - R01 AG043975/AG/NIA NIH HHS/United States
GR  - R01 NS088137/NS/NINDS NIH HHS/United States
GR  - P01 AG003991/AG/NIA NIH HHS/United States
GR  - P50 AG005681/AG/NIA NIH HHS/United States
GR  - R01 AG054672/AG/NIA NIH HHS/United States
GR  - Z01 AG000399/Intramural NIH HHS/United States
GR  - R01 AG051812/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Immunity
JT  - Immunity
JID - 9432918
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Apolipoproteins E)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Trem2 protein, mouse)
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
SB  - IM
CIN - Immunity. 2017 Sep 19;47(3):398-400. PMID: 28930654
MH  - Alzheimer Disease/genetics/metabolism/pathology
MH  - Amyloid beta-Peptides/metabolism
MH  - Amyloid beta-Protein Precursor/metabolism
MH  - Animals
MH  - Apolipoproteins E/deficiency/genetics/*metabolism
MH  - Apoptosis/genetics/immunology
MH  - Cerebral Cortex/metabolism/pathology
MH  - Cluster Analysis
MH  - Disease Models, Animal
MH  - Encephalomyelitis, Autoimmune, Experimental
MH  - Female
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - Gene Targeting
MH  - Humans
MH  - Immune Tolerance
MH  - Membrane Glycoproteins/*metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Microglia/immunology/*metabolism
MH  - Monocytes/immunology/metabolism
MH  - Neurodegenerative Diseases/*genetics/immunology/*metabolism
MH  - Neurons/metabolism
MH  - Phagocytosis/genetics/immunology
MH  - Phenotype
MH  - Plaque, Amyloid/metabolism/pathology
MH  - Receptors, Immunologic/*metabolism
MH  - *Signal Transduction
MH  - Superoxide Dismutase-1/genetics/metabolism
MH  - *Transcriptome
MH  - Transforming Growth Factor beta/metabolism
PMC - PMC5719893
MID - NIHMS901481
OTO - NOTNLM
OT  - APOE
OT  - Alzheimer's disease
OT  - TREM2
OT  - amyotrophic lateral sclerosis
OT  - microglia
OT  - multiple sclerosis
OT  - neurodegeneration
OT  - transcriptional regulation
COIS- Competing financial interests: CH: Roche advisor and collaborator. All other 
      authors declare no conflict of interests.
EDAT- 2017/09/21 06:00
MHDA- 2017/10/19 06:00
PMCR- 2018/09/19
CRDT- 2017/09/21 06:00
PHST- 2017/03/02 00:00 [received]
PHST- 2017/07/06 00:00 [revised]
PHST- 2017/08/17 00:00 [accepted]
PHST- 2017/09/21 06:00 [entrez]
PHST- 2017/09/21 06:00 [pubmed]
PHST- 2017/10/19 06:00 [medline]
PHST- 2018/09/19 00:00 [pmc-release]
AID - S1074-7613(17)30366-7 [pii]
AID - 10.1016/j.immuni.2017.08.008 [doi]
PST - ppublish
SO  - Immunity. 2017 Sep 19;47(3):566-581.e9. doi: 10.1016/j.immuni.2017.08.008.