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

被引：1865

作者：

Krasemann, Susanne ^{[1
,2
]}

Madore, Charlotte ^{[1
]}

Cialic, Ron ^{[1
]}

Baufeld, Caroline ^{[1
]}

Calcagno, Narghes ^{[1
]}

El Fatimy, Rachid ^{[1
]}

Beckers, Lien ^{[1
]}

O'Loughlin, Elaine ^{[1
]}

Xu, Yang ^{[3
]}

Fanek, Zain ^{[1
]}

Greco, David J. ^{[1
]}

Smith, Scott T. ^{[1
]}

Tweet, George ^{[1
]}

Humulock, Zachary ^{[1
]}

Zrzavy, Tobias ^{[4
]}

Conde-Sanroman, Patricia ^{[5
]}

Gacias, Mar ^{[5
]}

Weng, Zhiping ^{[6
]}

Chen, Hao ^{[6
]}

Tjon, Emily ^{[1
]}

Mazaheri, Fargol ^{[7
]}

Hartmann, Kristin ^{[2
]}

Madi, Asaf ^{[1
]}

Ulrich, Jason D. ^{[8
]}

Glatzel, Markus ^{[2
]}

Worthmann, Anna ^{[9
]}

Heeren, Joerg ^{[9
]}

Budnik, Bogdan ^{[10
]}

Lemere, Cynthia ^{[1
]}

Ikezu, Tsuneya ^{[11
,12
]}

Heppner, Frank L. ^{[13
,14
]}

Litvak, Vladimir ^{[3
]}

Holtzman, David M.

Lassmann, Hans ^{[4
]}

Weiner, Howard L. ^{[1
,15
]}

Ochando, Jordi ^{[5
]}

Haass, Christian ^{[7
,16
,17
]}

Butovsky, Oleg ^{[1
,15
]}

机构：

[1] Harvard Med Sch, Brigham & Womens Hosp, Dept Neurol, Ann Romney Ctr Neurol Dis, Boston, MA 02115 USA

[2] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany

[3] Univ Massachusetts, Med Sch, Dept Microbiol & Physiol Syst, Worcester, MA 01605 USA

[4] Med Univ Vienna, Ctr Brain Res, Vienna, Austria

[5] Icahn Sch Med Mt Sinai, Dept Med, New York, NY 10029 USA

[6] Univ Massachusetts, Med Sch, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA

[7] German Ctr Neurodegenerat Dis, Munich, Germany

[8] Washington Univ, Sch Med, Knight Alzheimers Dis Res Ctr, Hope Ctr Neurol Disorders,Dept Neurol, St Louis, MO 63108 USA

[9] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, Hamburg, Germany

[10] Harvard Univ, Fac Arts & Sci, Div Sci, Mass Spectrometry & Prote Resource Lab, Cambridge, MA 02138 USA

[11] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02215 USA

[12] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA

[13] Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany

[14] NeuroCure, Cluster Excellence, CharitePl 1, D-10117 Berlin, Germany

[15] Harvard Med Sch, Brigham & Womens Hosp, Evergrande Ctr Immunol Dis, Boston, MA 02115 USA

[16] Ludwig Maximilians Univ Munchen, Biomed Ctr, Biochem, Munich, Germany

[17] Munich Cluster Syst Neurol, Munich, Germany

来源：

IMMUNITY | 2017年 / 47卷 / 03期

基金：

欧洲研究理事会; 奥地利科学基金会;

关键词：

GENE-EXPRESSION SIGNATURE; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; MOUSE MODEL; CELLS; DEFICIENCY; MACROPHAGE; DEGENERATION; PROGRESSION; ACTIVATION;

D O I：

10.1016/j.immuni.2017.08.008

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 b-amyloid (Ab)-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.

引用

页码：566 / +

页数：25

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