Journal Article

DZNE-2020-05835

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.

Krasemann, S. ; Madore, C. ; Cialic, R. ; Baufeld, C. ; Calcagno, N. ; El Fatimy, R. ; Beckers, L. ; O'Loughlin, E. ; Xu, Y. ; Fanek, Z. ; Greco, D. J. ; Smith, S. T. ; Tweet, G. ; Humulock, Z. ; Zrzavy, T. ; Conde-Sanroman, P. ; Gacias, M. ; Weng, Z. ; Chen, H. ; Tjon, E. ; Mazaheri, F.DZNE* ; Hartmann, K. ; Madi, A. ; Ulrich, J. D. ; Glatzel, M. ; Worthmann, A. ; Heeren, J. ; Budnik, B. ; Lemere, C. ; Ikezu, T. ; Heppner, F. L. ; Litvak, V. ; Holtzman, D. M. ; Lassmann, H. ; Weiner, H. L. ; Ochando, J. ; Haass, C.DZNE* ; Butovsky, O. (Corresponding author)

2017
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.immuni.2017.08.008

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.

Keyword(s): Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloid beta-Protein Precursor: metabolism (MeSH) ; Animals (MeSH) ; Apolipoproteins E: deficiency (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Apolipoproteins E: metabolism (MeSH) ; Apoptosis: genetics (MeSH) ; Apoptosis: immunology (MeSH) ; Cerebral Cortex: metabolism (MeSH) ; Cerebral Cortex: pathology (MeSH) ; Cluster Analysis (MeSH) ; Disease Models, Animal (MeSH) ; Encephalomyelitis, Autoimmune, Experimental (MeSH) ; Female (MeSH) ; Gene Expression Profiling (MeSH) ; Gene Expression Regulation (MeSH) ; Gene Targeting (MeSH) ; Humans (MeSH) ; Immune Tolerance (MeSH) ; Membrane Glycoproteins: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Mice, Transgenic (MeSH) ; Microglia: immunology (MeSH) ; Microglia: metabolism (MeSH) ; Monocytes: immunology (MeSH) ; Monocytes: metabolism (MeSH) ; Neurodegenerative Diseases: genetics (MeSH) ; Neurodegenerative Diseases: immunology (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Phagocytosis: genetics (MeSH) ; Phagocytosis: immunology (MeSH) ; Phenotype (MeSH) ; Plaque, Amyloid: metabolism (MeSH) ; Plaque, Amyloid: pathology (MeSH) ; Receptors, Immunologic: metabolism (MeSH) ; Signal Transduction (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Superoxide Dismutase-1: metabolism (MeSH) ; Transcriptome (MeSH) ; Transforming Growth Factor beta: metabolism (MeSH) ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Apolipoproteins E ; Membrane Glycoproteins ; Receptors, Immunologic ; Transforming Growth Factor beta ; Trem2 protein, mouse ; Superoxide Dismutase-1

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 40 ; JCR ; Nationallizenz ; SCOPUS ; Web of Science Core Collection

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