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

被引：1753

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

共 58 条

[51] Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks
Trapnell, Cole
Roberts, Adam
Goff, Loyal
Pertea, Geo
Kim, Daehwan
Kelley, David R.
Pimentel, Harold
Salzberg, Steven L.
Rinn, John L.
Pachter, Lior
[J]. NATURE PROTOCOLS, 2012, 7 (03) : 562 - 578
[52] Cutting edge: TREM-2 attenuates macrophage activation
Turnbull, Isaiah R.
Gilfillan, Susan
Cella, Marina
Aoshi, Taiki
Miller, Mark
Piccio, Laura
Hernandez, Maristela
Colonna, Marco
[J]. JOURNAL OF IMMUNOLOGY, 2006, 177 (06) : 3520 - 3524
[53] Peroxisomal multifunctional protein-2 deficiency causes neuroinflammation and degeneration of Purkinje cells independent of very long chain fatty acid accumulation
Verheijden, Simon
Bottelbergs, Astrid
Krysko, Olga
Krysko, Dmitri V.
Beckers, Lien
De Munter, Stephanie
Van Veldhoven, Paul P.
Wyns, Sabine
Kulik, Wim
Nave, Klaus-Armin
Ramer, Matt S.
Carmeliet, Peter
Kassmann, Celia M.
Baes, Myriam
[J]. NEUROBIOLOGY OF DISEASE, 2013, 58 : 258 - 269
[54] Genetic Dissection of Tissue-Specific Apolipoprotein E Function for Hypercholesterolemia and Diet-Induced Obesity
Wagner, Tobias
Bartelt, Alexander
Schlein, Christian
Heeren, Joerg
[J]. PLOS ONE, 2015, 10 (12):
[55] TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Wang, Yaming
Ulland, Tyler K.
Ulrich, Jason D.
Song, Wilbur
Tzaferis, John A.
Hole, Justin T.
Yuan, Peng
Mahan, Thomas E.
Shi, Yang
Gilfillan, Susan
Cella, Marina
Grutzendler, Jaime
DeMattos, Ronald B.
Cirrito, John R.
Holtzman, David M.
Colonna, Marco
[J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2016, 213 (05) : 667 - 675
[56] TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer's Disease Model
Wang, Yaming
Cella, Marina
Mallinson, Kaitlin
Ulrich, Jason D.
Young, Katherine L.
Robinette, Michelle L.
Gilfillan, Susan
Krishnan, Gokul M.
Sudhakar, Shwetha
Zinselmeyer, Bernd H.
Holtzman, David M.
Cirrito, John R.
Colonna, Marco
[J]. CELL, 2015, 160 (06) : 1061 - 1071
[57] Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus
Xu, Qin
Bernardo, Aubrey
Walker, David
Kanegawa, Tiffany
Mahley, Robert W.
Huang, Yadong
[J]. JOURNAL OF NEUROSCIENCE, 2006, 26 (19) : 4985 - 4994
[58] TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy (vol 90, pg 724, 2016)
Yuan, Peng
Condello, Carlo
Keene, C. Dirk
Wang, Yaming
Bird, Thomas D.
Paul, Steven M.
Luo, Wenjie
Colonna, Marco
Baddeley, David
Grutzendler, Jaime
[J]. NEURON, 2016, 92 (01) : 252 - 264

← 1 2 3 4 5 6 →