TREM2

Synonyms

TREM-2, Triggering receptor expressed on monocytes 2, PLOSL2, Trem2b, Trem2a, Trem2c, Triggering Receptor Expressed On Myeloid Cells 2a

Description

TREM2 can forms a receptor signaling complex with TYROBP which mediates signaling and cell activation following ligand binding. Acts as a receptor for amyloid-beta protein 42, a cleavage product of the amyloid-beta precursor protein APP, and mediates its uptake and degradation by microglia. Binding to amyloid-beta 42 mediates microglial activation, proliferation, migration, apoptosis and expression of pro-inflammatory cytokines, such as IL6R and CCL3, and the anti-inflammatory cytokine ARG1. Acts as a receptor for lipoprotein particles such as LDL, VLDL, and HDL and for apolipoproteins such as APOA1, APOA2, APOB, APOE, APOE2, APOE3, APOE4, and CLU and enhances their uptake in microglia. Binds phospholipids (preferably anionic lipids) such as phosphatidylserine, phosphatidylethanolamine, phosphatidylglycerol and sphingomyelin. Regulates microglial proliferation by acting as an upstream regulator of the Wnt/beta-catenin signaling cascade. Required for microglial phagocytosis of apoptotic neurons. Also required for microglial activation and phagocytosis of myelin debris after neuronal injury and of neuronal synapses during synapse elimination in the developing brain. Regulates microglial chemotaxis and process outgrowth, and also the microglial response to oxidative stress and lipopolysaccharide. It suppresses PI3K and NF-kappa-B signaling in response to lipopolysaccharide; thus promoting phagocytosis, suppressing pro-inflammatory cytokine and nitric oxide production, inhibiting apoptosis and increasing expression of IL10 and TGFB. During oxidative stress, it promotes anti-apoptotic NF-kappa-B signaling and ERK signaling. Plays a role in microglial MTOR activation and metabolism. Regulates age-related changes in microglial numbers. Triggers activation of the immune responses in macrophages and dendritic cells. Mediates cytokine-induced formation of multinucleated giant cells which are formed by the fusion of macrophages. In dendritic cells, it mediates up-regulation of chemokine receptor CCR7 and dendritic cell maturation and survival. Involved in the positive regulation of osteoclast differentiation.

KO Status

RenMab: Antibody Discovery

RenLite: Antibody Discovery

Drug Information

Drug in clinical trials: 1
Latest Research Phase: Phase 2 Clinical

Drug Name

Code

Phase

Company

Indications

Clinical Trials

AL-002

AL-002

Phase 2 Clinical

Alector

Alzheimer Disease

DNL-919

DNL-919

Preclinical

Denali Therapeutics Inc

Alzheimer Disease

VGL-101

VGL-101, VGL 101

Preclinical

Amgen Inc

Nerve Degeneration

References


Title

Authors

Source

TREM2 Is a Receptor for beta-Amyloid that Mediates Microglial Function

Zhao Y., Wu X., Li X., Jiang L.L., Gui X., Liu Y., Sun Y., Zhu B., Pina-Crespo J.C., Zhang M., Zhang N., Chen X., Bu G., An Z., Huang T.Y., Xu H.,

Neuron 97:1023-1031(2018)

Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms

Kober D.L., Alexander-Brett J.M., Karch C.M., Cruchaga C., Colonna M., Holtzman M.J., Brett T.J.,

Elife 5:E20391-E20391(2016)

Molecular basis for the loss-of-function effects of the Alzheimer's disease-associated R47H variant of the immune receptor TREM2

Sudom A., Talreja S., Danao J., Bragg E., Kegel R., Min X., Richardson J., Zhang Z., Sharkov N., Marcora E., Thibault S., Bradley J., Wood S., Lim A.C., Chen H., Wang S., Foltz I.N., Sambashivan S., Wang Z.,

J. Biol. Chem. 293:12634-12646(2018)

An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene

Soragna D., Papi L., Ratti M.T., Sestini R., Tupler R., Montalbetti L.,

J. Neurol. Neurosurg. Psych. 74:825-826(2003)

Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL): a new report of an Italian woman and review of the literature

Bock V., Botturi A., Gaviani P., Lamperti E., Maccagnano C., Piccio L., Silvani A., Salmaggi A.,

J. Neurol. Sci. 326:115-119(2013)

Disease-associated mutations of TREM2 alter the processing of N-linked oligosaccharides in the Golgi apparatus

Park J.S., Ji I.J., An H.J., Kang M.J., Kang S.W., Kim D.H., Yoon S.Y.,

Traffic 16:510-518(2015)

Evidence of CNS beta-amyloid deposition in Nasu-Hakola disease due to the TREM2 Q33X mutation

Ghezzi L., Carandini T., Arighi A., Fenoglio C., Arcaro M., De Riz M., Pietroboni A.M., Fumagalli G.G., Basilico P., Calvi A., Scarioni M., Colombi A., Serpente M., Marotta G., Benti R., Scarpini E., Galimberti D.,

Neurology 89:2503-2505(2017)

Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes

Bouchon A., Dietrich J., Colonna M.,

J. Immunol. 164:4991-4995(2000)

The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)

The MGC Project Team,

Genome Res. 14:2121-2127(2004)

A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells

Bouchon A., Hernandez-Munain C., Cella M., Colonna M.,

J. Exp. Med. 194:1111-1122(2001)