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

Susanne Krasemann; Charlotte Madore; Ron Cialic; Caroline Baufeld; Narghes Calcagno; Rachid El Fatimy; Lien Beckers; Elaine O'Loughlin; Yang Xu; Zain Fanek; David J Greco; Scott T Smith; George Tweet; Zachary Humulock; Tobias Zrzavy; Patricia Conde-Sanroman; Mar Gacias; Zhiping Weng; Hao Chen; Emily Tjon; Fargol Mazaheri; Kristin Hartmann; Asaf Madi; Jason D Ulrich; Markus Glatzel; Anna Worthmann; Joerg Heeren; Bogdan Budnik; Cynthia Lemere; Tsuneya Ikezu; Frank L Heppner; Vladimir Litvak; David M Holtzman; Hans Lassmann; Howard L Weiner; Jordi Ochando; Christian Haass; Oleg Butovsky

doi:10.1016/j.immuni.2017.08.008

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

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

Authors

Susanne Krasemann¹, Charlotte Madore², Ron Cialic², Caroline Baufeld², Narghes Calcagno², Rachid El Fatimy², Lien Beckers², Elaine O'Loughlin², Yang Xu³, Zain Fanek², David J Greco², Scott T Smith², George Tweet², Zachary Humulock², Tobias Zrzavy⁴, Patricia Conde-Sanroman⁵, Mar Gacias⁵, Zhiping Weng⁶, Hao Chen⁶, Emily Tjon², Fargol Mazaheri⁷, Kristin Hartmann⁸, Asaf Madi², Jason D Ulrich⁹, Markus Glatzel⁸, Anna Worthmann¹⁰, Joerg Heeren¹⁰, Bogdan Budnik¹¹, Cynthia Lemere², Tsuneya Ikezu¹², Frank L Heppner¹³, Vladimir Litvak³, David M Holtzman⁹, Hans Lassmann⁴, Howard L Weiner¹⁴, Jordi Ochando⁵, Christian Haass¹⁵, Oleg Butovsky¹⁶

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / metabolism
Animals
Apolipoproteins E / deficiency
Apolipoproteins E / genetics
Apolipoproteins E / metabolism*
Apoptosis / genetics
Apoptosis / immunology
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Cluster Analysis
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
Female
Gene Expression Profiling
Gene Expression Regulation
Gene Targeting
Humans
Immune Tolerance
Membrane Glycoproteins / metabolism*
Mice
Mice, Knockout
Mice, Transgenic
Microglia / immunology
Microglia / metabolism*
Monocytes / immunology
Monocytes / metabolism
Neurodegenerative Diseases / genetics*
Neurodegenerative Diseases / immunology
Neurodegenerative Diseases / metabolism*
Neurons / metabolism
Phagocytosis / genetics
Phagocytosis / immunology
Phenotype
Plaque, Amyloid / metabolism
Plaque, Amyloid / pathology
Receptors, Immunologic / metabolism*
Signal Transduction*
Superoxide Dismutase-1 / genetics
Superoxide Dismutase-1 / metabolism
Transcriptome*
Transforming Growth Factor beta / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Apolipoproteins E
Membrane Glycoproteins
Receptors, Immunologic
Transforming Growth Factor beta
Trem2 protein, mouse
Superoxide Dismutase-1

Abstract

Publication types

MeSH terms

Substances

Grants and funding