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

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The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. / Krasemann, Susanne; Madore, Charlotte; Cialic, Ron; Baufeld, Caroline; Calcagno, Narghes; El Fatimy, Rachid; Beckers, Lien; O'Loughlin, Elaine; Xu, Yang; Fanek, Zain; Greco, David J; Smith, Scott T; Tweet, George; Humulock, Zachary; Zrzavy, Tobias; Conde-Sanroman, Patricia; Gacias, Mar; Weng, Zhiping; Chen, Hao; Tjon, Emily; Mazaheri, Fargol; Hartmann, Kristin; Madi, Asaf; Ulrich, Jason D; Glatzel, Markus; Worthmann, Anna; Heeren, Joerg; Budnik, Bogdan; Lemere, Cynthia; Ikezu, Tsuneya; Heppner, Frank L; Litvak, Vladimir; Holtzman, David M; Lassmann, Hans; Weiner, Howard L; Ochando, Jordi; Haass, Christian; Butovsky, Oleg.

In: IMMUNITY, Vol. 47, No. 3, 19.09.2017, p. 566-581.e9.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Krasemann, S, Madore, C, Cialic, R, Baufeld, C, Calcagno, N, El Fatimy, R, Beckers, L, O'Loughlin, E, Xu, Y, Fanek, Z, Greco, DJ, Smith, ST, Tweet, G, Humulock, Z, Zrzavy, T, Conde-Sanroman, P, Gacias, M, Weng, Z, Chen, H, Tjon, E, Mazaheri, F, Hartmann, K, Madi, A, Ulrich, JD, Glatzel, M, Worthmann, A, Heeren, J, Budnik, B, Lemere, C, Ikezu, T, Heppner, FL, Litvak, V, Holtzman, DM, Lassmann, H, Weiner, HL, Ochando, J, Haass, C & Butovsky, O 2017, 'The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases', IMMUNITY, vol. 47, no. 3, pp. 566-581.e9. https://doi.org/10.1016/j.immuni.2017.08.008

APA

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., ... Butovsky, O. (2017). The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. IMMUNITY, 47(3), 566-581.e9. https://doi.org/10.1016/j.immuni.2017.08.008

Vancouver

Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. IMMUNITY. 2017 Sep 19;47(3):566-581.e9. https://doi.org/10.1016/j.immuni.2017.08.008

Bibtex

@article{c734aeba4cb34d4bb409459b05068a04,
title = "The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases",
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 = "Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Apolipoproteins E, Apoptosis, Cerebral Cortex, Cluster Analysis, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Targeting, Humans, Immune Tolerance, Membrane Glycoproteins, Mice, Mice, Knockout, Mice, Transgenic, Microglia, Monocytes, Neurodegenerative Diseases, Neurons, Phagocytosis, Phenotype, Plaque, Amyloid, Receptors, Immunologic, Signal Transduction, Superoxide Dismutase-1, Transcriptome, Transforming Growth Factor beta, Journal Article",
author = "Susanne Krasemann and Charlotte Madore and Ron Cialic and Caroline Baufeld and Narghes Calcagno and {El Fatimy}, Rachid and Lien Beckers and Elaine O'Loughlin and Yang Xu and Zain Fanek and Greco, {David J} and Smith, {Scott T} and George Tweet and Zachary Humulock and Tobias Zrzavy and Patricia Conde-Sanroman and Mar Gacias and Zhiping Weng and Hao Chen and Emily Tjon and Fargol Mazaheri and Kristin Hartmann and Asaf Madi and Ulrich, {Jason D} and Markus Glatzel and Anna Worthmann and Joerg Heeren and Bogdan Budnik and Cynthia Lemere and Tsuneya Ikezu and Heppner, {Frank L} and Vladimir Litvak and Holtzman, {David M} and Hans Lassmann and Weiner, {Howard L} and Jordi Ochando and Christian Haass and Oleg Butovsky",
note = "Copyright {\textcopyright} 2017 Elsevier Inc. All rights reserved.",
year = "2017",
month = sep,
day = "19",
doi = "10.1016/j.immuni.2017.08.008",
language = "English",
volume = "47",
pages = "566--581.e9",
journal = "IMMUNITY",
issn = "1074-7613",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases

AU - Krasemann, Susanne

AU - Madore, Charlotte

AU - Cialic, Ron

AU - Baufeld, Caroline

AU - Calcagno, Narghes

AU - El Fatimy, Rachid

AU - Beckers, Lien

AU - O'Loughlin, Elaine

AU - Xu, Yang

AU - Fanek, Zain

AU - Greco, David J

AU - Smith, Scott T

AU - Tweet, George

AU - Humulock, Zachary

AU - Zrzavy, Tobias

AU - Conde-Sanroman, Patricia

AU - Gacias, Mar

AU - Weng, Zhiping

AU - Chen, Hao

AU - Tjon, Emily

AU - Mazaheri, Fargol

AU - Hartmann, Kristin

AU - Madi, Asaf

AU - Ulrich, Jason D

AU - Glatzel, Markus

AU - Worthmann, Anna

AU - Heeren, Joerg

AU - Budnik, Bogdan

AU - Lemere, Cynthia

AU - Ikezu, Tsuneya

AU - Heppner, Frank L

AU - Litvak, Vladimir

AU - Holtzman, David M

AU - Lassmann, Hans

AU - Weiner, Howard L

AU - Ochando, Jordi

AU - Haass, Christian

AU - Butovsky, Oleg

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2017/9/19

Y1 - 2017/9/19

N2 - 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.

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 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.

KW - Alzheimer Disease

KW - Amyloid beta-Peptides

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Apolipoproteins E

KW - Apoptosis

KW - Cerebral Cortex

KW - Cluster Analysis

KW - Disease Models, Animal

KW - Encephalomyelitis, Autoimmune, Experimental

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Gene Targeting

KW - Humans

KW - Immune Tolerance

KW - Membrane Glycoproteins

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Microglia

KW - Monocytes

KW - Neurodegenerative Diseases

KW - Neurons

KW - Phagocytosis

KW - Phenotype

KW - Plaque, Amyloid

KW - Receptors, Immunologic

KW - Signal Transduction

KW - Superoxide Dismutase-1

KW - Transcriptome

KW - Transforming Growth Factor beta

KW - Journal Article

U2 - 10.1016/j.immuni.2017.08.008

DO - 10.1016/j.immuni.2017.08.008

M3 - SCORING: Journal article

C2 - 28930663

VL - 47

SP - 566-581.e9

JO - IMMUNITY

JF - IMMUNITY

SN - 1074-7613

IS - 3

ER -