Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Atagi, Yuka; Liu, Chia-Chen; Painter, Meghan M.; Chen, Xiao Fen; Verbeeck, Christophe; Zheng, Honghua; Li, Xia; Rademakers, Rosa; Kang, Silvia S.; Xu, Huaxi; Younkin, Steven G.; Das, Pritam; Fryer, John Denis; Bu, Guojun

doi:10.1074/jbc.m115.679043

Cited by 450 publications

(481 citation statements)

References 55 publications

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“…genes involved in cholesterol transport and efferocytosis (Apoe), immunoproteasome formation (Psmb9 and Pbmb8), and efferocytosis and the resolution of inflammation (Anxa1) (43)(44)(45). Taken together, these results show that this set of genes may be responsible for maintaining a reparative phenotype of MDMs.…”

Section: Resultsmentioning

confidence: 83%

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

140

161

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-/-bone marrow chimeras (BMCs) at days 7 and 15 after ICH. Right: Quantification of residual hematoma volume in the WT and Ccr2 -/-BMCs. n = 11 at day 7; n = 9 at day 15. *P < 0.05 by Student's t test. (B) Cylinder test and apomorphine turning test from WT and Ccr2 -/-BMCs at day 15 after ICH. n = 6/group for cylinder test; n = 8/ group for apomorphine turning test. *P < 0.05 by Student's t test. (C) Cylinder test, neurological deficit score, and corner test in control-and anti-CCR2 antibody-treated mice at days 1 and 3 after collagenase ICH. n = 7/group. *P < 0.05 by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. (D) Top: Representative coronal sections show hematoma from control-and anti-CCR2 antibody-treated WT mice after blood injection ICH at 7 days. Bottom: Quantification of hematoma volume, n = 3/ group. *P < 0.05 versus control by Student's t test. (E) Top: Representative coronal sections show hematoma in the isotype control-and anti-CCR2 antibody-treated mice from collagenase model at day 12. Bottom: Quantification of hematoma volume. n = 8/group. *P < 0.05 versus control by Student's t test. (F) The cylinder test, neurological deficit score, and corner test in isotype control-and anti-CCR2 antibody-treated ICH mice at days 3, 5, 7, 9, and 11 after collagenase ICH surgery. n = 8/group. *P < 0.05 versus isotype control group by 1-way repeated-measures ANOVA and Bonferroni's post hoc test. αCCR2, anti-CCR2 antibody.

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Section: Resultsmentioning

confidence: 83%

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Chang¹,

Goods²,

Askenase³

et al. 2017

Journal of Clinical Investigation

140

161

View full text Add to dashboard Cite

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“…Several different ligands for TREM2 have been reported previously including apolipoprotein E (Atagi et al, 2015;Bailey et al, 2015), lipids exposed upon axonal injury (Poliani et al, 2015), nucleic acids released from dying cells (Kawabori et al, 2015) and damage-associated molecular signatures found on bacteria (Daws et al, 2003;N'Diaye et al, 2009). Interestingly, the ADassociated TREM2 R47H variant shows impaired binding to apolipoprotein E or injury-associated lipids (Atagi et al, 2015;Bailey et al, 2015;Poliani et al, 2015). Hence, we speculate that the glycosylation status changes we observed herein for the R47H variant (Figures 1-3) could explain the ligand binding differences between wild-type TREM2 and TREM2 R47H (Atagi et al, 2015;Bailey et al, 2015;Poliani et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the ADassociated TREM2 R47H variant has impaired binding to the apolipoprotein E or injury-associated lipids (Atagi et al, 2015;Bailey et al, 2015;Poliani et al, 2015). However, it is still unknown how this impairment occurs, or how this may relate to AD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

[P4–449]: The Alzheimer's Disease‐associated R47h Variant of Trem2 Has an Altered Glycosylation Pattern and Protein Stability

Park

Kim

et al. 2017

Alzheimer's & Dementia

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The R47H coding variant of the triggering receptor expressed on myeloid cells-2 (TREM2) increases the risk of Alzheimer's disease (AD) similar to apolipoprotein E4. TREM2 R47H has recently been shown to have impaired binding to damage-associated lipid or apolipoprotein ligands. However, it is not known how this R47H variant affects the biochemical characteristics of TREM2 and alters the pathogenesis of AD. We previously reported that TREM2-R47H has a slightly different glycosylation pattern from wild-type. A more detailed characterization in our present study confirms that TREM2 R47H has an altered glycosylation pattern and reduced stability. TREM2 R47H shows different glycosylation profiles from analysis using monensin or kifunensine treatment which were confirmed by mass spectrometry. The solubility of TREM2 R47H and its cleaved products such as intracellular domain (ICD) is also decreased, increasing its proteasomal and lysosomal degradation. The different biochemical characteristics of TREM2 R47H, including glycosylation, solubility and processing, may offer insights into a future therapeutic strategy for AD.

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“…TREM2 could serve as a microglial sensor for lipid mediators that are released from damaged sensory nerve terminals or other cells in the DH. Recently, apolipoprotein E (ApoE) was reported to be a potent ligand for TREM2, and an Alzheimer's diseaseassociated R47H mutation and other artificial mutations introduced at the same location significantly reduce the affinity of TREM2 for ApoE (Atagi et al, 2015;Bailey et al, 2015). Additionally, ApoE protein was shown to be upregulated in injured DRG neurons in a spinal nerve ligation model (Melemedjian et al, 2013).…”

Section: Trem2 Functionmentioning

confidence: 99%

TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain

et al. 2016

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Neuropathic pain afflicts millions of people, and the development of an effective treatment for this intractable pain is an urgent issue. Recent evidence has implicated microglia in neuropathic pain. The present study showed that the DNAX-activating protein of 12 kDa (DAP12) and its associated "triggering receptor expressed on myeloid cells 2" (TREM2) were predominantly expressed by microglia in the dorsal horn after spinal nerve injury, revealing a role for TREM2/DAP12 signaling in neuropathic pain. Nerve injury-induced proinflammatory cytokine expression in microglia and pain behaviors were significantly suppressed in Dap12-deficient mice. Furthermore, intrathecal administration of TREM2 agonistic antibody induced proinflammatory cytokine expression, as well as neuropathic pain, in mice without nerve injury. The agonistic antibody induced proinflammatory responses and neuropathic pain was not observed in Dap12-deficient mice. Together, these results suggest that TREM2/DAP12-mediated signals in microglia exacerbate nerve injuryinduced neuropathic pain by inducing proinflammatory cytokine secretion from microglia. Suppression of DAP12-mediated signals could be a therapeutic target for neuropathic pain.

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Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Cited by 450 publications

References 55 publications

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

[P4–449]: The Alzheimer's Disease‐associated R47h Variant of Trem2 Has an Altered Glycosylation Pattern and Protein Stability

TREM2/DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain

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