Alzheimer’s disease is a neurodegenerative disease and the most common cause of dementia – characterized by memory loss and difficulties with thinking, problem solving and language – in the elderly. Individuals with rare mutations in the gene that encodes a protein called TREM2 have a substantial risk of developing Alzheimer’s disease in their mid-60s. A different set of mutations in the gene for TREM2 can cause a more severe degenerative brain disease known as Nasu-Hakola disease in much younger people.

Proteins are made up of chains of building blocks called amino acids that need to fold into specific three-dimensional shapes to allow the protein to work properly. TREM2 is a signaling protein that is found on the surface of immune cells in the brain. Mutations causing Alzheimer’s and Nasu-Hakola disease result in the production of mutant TREM2 proteins that differ from the normal protein by only a single amino acid. It is not clear how different mutations affecting the same protein can give rise to two distinct neurodegenerative diseases.

To address this question, Kober et al. used a range of techniques to study normal and mutant TREM2 proteins. First, a technique called X-ray crystallography – which makes it possible to construct three-dimensional models of proteins – revealed that the mutations responsible for Nasu-Hakola disease are buried deep within the core of the folded TREM2 protein. On the other hand, mutations associated with Alzheimer’s disease lie on the surface of the protein.

Further experiments examined how these mutations alter the properties of TREM2, revealing that mutations linked to Nasu-Hakola disease affect the ability of TREM2 to fold correctly and how stable its final shape is. This results in fewer TREM2 proteins being present on the surface of immune cells. In contrast, mutations associated with Alzheimer’s disease make it harder for TREM2 to bind to molecules known as glycosaminoglycans. The Alzheimer’s mutations affect a specific part of TREM2 that is not found in other closely related proteins.

The findings of Kober et al. suggest that TREM2 binding to glycosaminoglycans is likely to be important in preventing Alzheimer’s disease. The next step following on from this work is to find out exactly how these interactions affect immune cells, which may aid the development of new therapies for this disease.

The precise molecular determinants and mechanisms underlying neurodegenerative diseases remain uncertain, but recent large-scale genetic sequencing projects have uncovered new candidates associated with these diseases. For example, whole genome and whole exome sequencing has identified point mutations in the gene encoding the protein TREM2 (triggering receptor expressed on myeloid cells 2) that correlate with a significantly increased risk of developing Alzheimer’s disease (AD) (Guerreiro et al., 2013b; Jonsson et al., 2013). In particular, the TREM2 R47H variant is associated with a risk that is similar to that associated with APOE4, previously the only well-established risk factor for late-onset AD. This mutation correlates with increased cerebrospinal fluid (CSF) tau levels, a well-established risk factor for AD (Cruchaga et al., 2013), and subsequent studies have identified this mutation in patients who have frontal temporal dementia (FTD), Parkinson’s disease (PD) (Rayaprolu et al., 2013), and sporadic amyotrophic lateral sclerosis (ALS) (Cady et al., 2014). A recent study of more than 1,600 late-onset AD (LOAD) and cognitively normal brains revealed that microglia-specific networks, including those containing TREM2, are those most significantly dysregulated in LOAD (Zhang et al., 2013). Thus, even in the absence of rare variants in TREM2 that increase AD risk, TREM2-containing pathways play a significant role in disease. Recent studies in AD mouse models that are deficient in TREM2 confirm that loss of TREM2 function contributes to classic AD pathology and demonstrates a crucial role for TREM2 in central nervous system (CNS) biology (Jay et al., 2015; Wang et al., 2015; Ulrich et al., 2014). TREM2-deficient AD mice display fewer activated microglia, and the absence of TREM2 prevents microglia proliferation and promotes microglia apoptosis, which was correlated with increased accumulation of Aβ plaques (Wang et al., 2015; Jay et al., 2015). Microglia in TREM2-deficient AD mice displayed less activation and did not engulf Aβ plaques. This impacts the density of Aβ plaques and promotes diffuse Aβ structures, which in turn are more neurotoxic, and contributes to the accumulation of classic AD pathology (Wang et al., 2016; Yuan et al., 2016). These findings highlight a crucial role for TREM2 in maintaining CNS homeostasis. Therefore,understanding how these risk variants affect TREM2 function and contribute to the pathogenesis of neurodegenerative diseases is vital to the development of therapies targeting these devastating conditions.

TREM2 is an innate immune receptor expressed on dendritic cells (DCs), resident macrophages such as osteoclasts and microglia, infiltrating (Jay et al., 2015) and inflammatory (Wu et al., 2015) macrophages, and CSF monocytes (Colonna and Wang, 2016). It is a type one receptor protein consisting of an extracellular V-type Ig domain, a short stalk, a transmembrane domain that associates with the adaptor protein DAP12 for signaling, and a cytoplasmic tail (Figure 1a) (Colonna, 2003). TREM2 has historically been shown to play an anti-inflammatory role in vitro by antagonizing the production of inflammatory cytokines from bone-marrow-derived macrophages (BMDMs) and dendritic cells (BMDDCs) in response to FcR (Hamerman et al., 2006) and Tlr signaling (Turnbull et al., 2006; Ito and Hamerman, 2012). Likewise, TREM2 participates in phagocytosis of apoptotic cells in cultured microglia and reduces the production of inflammatory cytokines (Takahashi et al., 2005). However, TREM2-expressing macrophages can also promote inflammatory disease in the brain (Jay et al., 2015) and lung (Wu et al., 2015). The identity of a physiologic TREM2 ligand (TREM2-L) remains uncertain, although several classes of molecules have been proposed, including bacterial carbohydrates (Daws et al., 2003; Quan et al., 2008), sulfoglycolipids (Phongsisay et al., 2015), nucleic acids (Kawabori et al., 2015), phospholipids (Cannon et al., 2012; Wang et al., 2015) and proteins (Stefano et al., 2009; Takegahara et al., 2006; Yoon et al., 2012; Atagi et al., 2015; Bailey et al., 2015). Additionally, previous studies have identified cells that express a TREM2-L, including astrocytes (Daws et al., 2003), DCs (Ito and Hamerman, 2012), BMDMs (Hamerman et al., 2006), neurons and apoptotic cells (Hsieh et al., 2009). This growing body of literature underscores the case for immune deregulation, specifically involving TREM2-associated pathways in neurodegenerative and inflammatory diseases (Golde et al., 2013).

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Intriguingly, genetic variations in TREM2 are associated with two distinct groups of neurodegenerative diseases. Homozygous mutations including early-stop codons (Paloneva et al., 2003; Soragna et al., 2003), splice site mutations (Numasawa et al., 2011; Chouery et al., 2008), the coding stalk mutations D134G and K186N (Paloneva et al., 2002), and the coding ectodomain mutations Y38C, T66M, and V126G (Guerreiro et al., 2013a, 2013c; Le Ber et al., 2014) cause either NHD, characterized by early-onset dementia, demyelination, and bone cyst lipoma (Paloneva et al., 2002; Colonna, 2003), or a frontotemporal dementia variant with severe loss of brain matter but lacking the bone manifestations. By contrast, TREM2 mutations associated with AD contribute to disease risk as heterozygous variants. In addition to R47H, the coding mutation R62H is associated with increased risk of AD in independent studies (Jin et al., 2014; Ridge et al., 2016). These two variants have the strongest risk link to AD. N68K and D87N have also been identified in AD patients, but because these mutations are very rare, their risk remains uncertain (Guerreiro et al., 2013b; Jonsson et al., 2013). In addition, the mutation T96K has been linked to a decreased risk of AD, but this mutation is also too rare to allow verification of this observation (Jin et al., 2014). This curious segregation of disease phenotypes by distinct mutations occurring within the same protein suggest that these mutations should have divergent effects on the structure and function of TREM2.

In order to understand the molecular basis of how different mutations within TREM2 can lead to distinct neurodegenerative diseases, we performed structural, biophysical, and functional studies of wild-type (WT) and mutant TREM2 proteins. To facilitate these studies, we developed a novel mammalian expression system to produce the natively folded and glycosylated TREM2 ectodomains in milligram quantities (Kober et al., 2014, 2015). We determined the crystal structure of the TREM2 ectodomain at 3.1 Å resolution and found that the disease-linked mutations exhibit distinct structural patterns, suggesting that they would impact TREM2 function through alternate mechanisms. To investigate this hypothesis, we carried out extensive biophysical, cellular, and functional assays. We found that NHD-causing mutations impact TREM2 protein folding and stability, whereas AD risk variants decrease binding to the cellular TREM2-ligand (TREM2-L). Furthermore, these AD-linked mutations appear to epitope map a disease-relevant functional surface on TREM2 that facilitates binding to cell-surface TREM2-L. These findings demonstrate two distinct loss-of-function mechanisms for TREM2, illuminate a disease-relevant functional surface on TREM2, and pave the way for the development of patient-specific molecular therapies for the treatment of distinct neurodegenerative diseases.

Here we elucidate how distinct point mutations in TREM2 give rise to different neurodegenerative diseases via two separate loss-of-function mechanisms. Our studies indicate, as presaged by our crystal structure, that NHD-linked mutant residues are buried and impact protein folding and stability, while AD-linked variant residues are on the protein surface and do not diminish the stability or surface expression of the molecule but instead impact ligand engagement (Figure 6a). Several variants have been reported for TREM2, but some are very rare, so it is not clear whether they associate with AD risk. The structure-based studies presented here provide a framework with which one could make predictions as to the variant's impact on function. Our observation of detectable misfolded cell-surface TREM2 NHD mutant proteins was surprising, given that one would expect that the cellular quality-control machinery should degrade misfolded proteins and prevent their surface expression. In addition, previous reports noted decreased surface expression for these mutants (Park et al., 2015; Kleinberger et al., 2014). Here, we used an approach that probes surface expression using both non-conformational (anti-FLAG) and conformational (anti-hTREM2) antibodies. We found that both the NHD-associated and AD-linked mutant proteins reach the cell surface, however the NHD-associated TREM2 mutants are probably not functional as they are either misfolded or aggregated, and thus are not recognized by the conformational-dependent antibodies. These results are supported by our analysis of the solution behavior of theTREM2 ectodomains of these mutant proteins. An alternative explanation could be that the FLAG tag or overexpression drives the surface expression of these mutated proteins; but we do not think that is the case since we found that the TREM2 ectodomains carrying these mutations (which contain a different tag that is on the opposite terminus) were also secreted. These findings are of potential therapeutic value, as the discovery of molecular chaperones that rescue the folding of and restore function to these mutants could be pursued for patient-specific NHD treatments.

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In contrast to the buried NHD mutant proteins, the AD risk variants lie on the surface of the protein and do not severely impact the protein folding or stability of TREM2. However, it should be noted that the R47H mutation does induce a subtle change in secondary structure detectable by CD. The AD mutations probably alter TREM2 function by impairing ligand binding. Recent studies in AD mouse models that are deficient in TREM2 confirm that loss of TREM2 function contributes to classic AD pathology and suggest a crucial role for TREM2 in microglia function (Jay et al., 2015; Wang et al., 2015; Ulrich et al., 2014). TREM2-deficient AD mice display fewer activated microglia, and the absence of TREM2 prevents microglia proliferation and promotes microglia apoptosis, which is correlated with increased accumulation of Aβ plaques (Wang et al., 2015; Jay et al., 2015). Microglia in TREM2-deficient AD mice display less activation and do not engulf Aβ plaques, which reduces the density of Aβ plaques and promotes diffuse Aβ structures, which, in turn, are more neurotoxic and contribute to the accumulation of classic AD pathology (Wang et al., 2016; Yuan et al., 2016). These models suggest a crucial role for TREM2 in microglia biology and in the turnover of Aβ. On the basis of the conserved nature of AD-linked basic surface residues and our analysis of cell-surface ligand binding for multiple cell lines, we favor the concept that AD risk variants lead to impaired binding of TREM2-L, which in turn perturbs microglia function.

With this in mind, we investigated how AD risk variants in TREM2 affect binding to previously identified and newly hypothesized ligands based on the analysis of ourcrystal structure. The many diverse ligands reported for TREM2 may in fact suggest that TREM2 is capable of recognizing multiple ligands and that under different conditions, their respective affinities might tune signaling accordingly. For example, low-affinity ligands may induce a tonic inhibitory signal while ligation of a high-affinity ligand could result in an activating response. Indeed, anionic bacterial carbohydrates (Daws et al., 2003), phospholipids (Wang et al., 2015), myelin lipids (Poliani et al., 2015), and even purified DNA (Kawabori et al., 2015) all activate TREM2 reporter cell lines. This is not surprising in light of our crystal structure, which reveals an extended basic patch on the surface of TREM2 that would be capable of forming electrostatic interactions with these anionic ligands. In contrast to highly selective phospholipid binding by other Ig domains (Kobayashi et al., 2007; Miyanishi et al., 2007; Santiago et al., 2007; Simhadri et al., 2012), purified TREM2 shows only broad discrimination for anionic (PA, PG, PI, PS) over more neutral (PC, PE) lipids (Figure 4—figure supplement 1a,b and c). Structurally, Ig domains with selective lipid binding feature a canonical FG loop motif that contains large hydrophobic residues, absent in TREM2, which mediate membrane insertion and acyl chain binding (Tietjen et al., 2014) (Figure 4—figure supplement 1d,e). Moreover, while TREM2 does share a conserved aspartic acid residue from this motif, which chelates a required Ca²⁺ ion for the TIM and CD300a proteins, TREM2-lipid binding is not sensitive to EDTA, unlike TIM and CD300 (Figure 4—figure supplement 1e and f). Thus, while we do observe direct binding of TREM2 to phospholipids, it does not appear that TREM2 binds phospholipids with high selectivity or using the same binding mode as other phospholipid-binding Ig domains. By contrast, it should be noted that there is a long and narrow hydrophobic patch on the end of TREM2 most distal from the plasma membrane (Figure 6—figure supplement 1) that is the most likely lipid-binding surface. Interestingly this patch is adjacent to the basic patch, which could mediate interaction with anionic phospholipid head groups (Figure 6b). These hypotheses will need to be tested in future studies using sensitive binding assays (such as surface plasmon resonance) and crystallographic studies of TREM2-phospholipid recognition. In contrast to recent studies employing reporter cells expressing TREM2 R47H (Wang et al., 2015), we did not observe any large differences in binding to phospholipids for any of the validated TREM2 AD risk variants. In light of our experimental observations, we believe this is best explained by the hypothesis that another interaction (such as TREM2 binding to GAGs, which we show here is impacted by these AD risk variants) is required to mediate phospholipid signaling; thus in the context of cellular experiments, TREM2 R47H shows diminished signaling, while in direct lipid-binding assays it performs in the same way as WT TREM2. This is potentially supported by a recent report that TREM2 binds to isolated PS, but does not bind apoptotic Jurkat T cells, which present PS on their cell surface but may also be deficient in GAGs (Bailey et al., 2015). The results presented here suggest that the point mutations in TREM2 participate in neurodegenerative disease pathogenesis through distinct molecular mechanisms.

We found that the validated AD risk variants in TREM2 impact binding to a cell-surface ligand (TREM2-L). This ligand does appear to contain a protein component, as pre-treatment of cells with proteases decreases or prevents the binding of TREM2 to these cells. This interaction also appears to be highly GAG-mediated, as TREM2 cell-staining tetramers do not bind CHO 745 cells, which do not express GAGs. This interaction seems most dependent on heparan sulfate, as treatment with heparin sulfatases remove much of the observed binding. As the AD risk variants most notably impact binding to TREM2-L, we reason that this interaction is involved in the pathogenesis of AD. In support of this, we find that the mutations R47H and perhaps R62H deleteriously impact TREM2-L recognition. By contrast, T96K appears to be a potential gain-of-function mutation in our binding experiments. Interestingly, this mutation appears at a much higher frequency than R47H and R62H, and in some studies it has been reported to be enriched in European-American AD cases compared to controls; overall it is associated with a decreased odds ratio for the development of late-onset AD (Figure 1c), again suggesting the TREM2-L binding function is coupled to AD risk. Altogether, the structural and functional analysis of these variants illuminates a surface epitope that is specific to TREM2, that is not conserved among the other members of the TREM family, and that mediates binding to a cell-surface ligand. Additional point mutations localized to that surface also resulted in loss of binding, supporting this functional role. Our results suggest that this ligand may have a specific protein component in addition to GAGs. On that note, while this manuscript was in preparation, it was reported that TREM2 binds lipid-loaded ApoE and that this interaction facilitates uptake of Aβ loaded into lipoparticles by microglia (Yeh et al., 2016). This report also suggests that TREM2 AD risk variants decrease binding to ApoE, but binding affinities were not quantitated. However, we do not suspect that ApoE is the protein component of cell surface TREM2-L because it is a soluble rather than a surface-bound protein. Our study demonstrates that TREM2 can specifically bind GAGs, utilizing the basic patch; other TREM-like proteins with the same overall calculated pI, but lacking the basic patch residues, do not bind GAGs. We also demonstrate that TREM2 AD risk variants affect binding to GAGs. Future studies will need to focus on how TREM2 binding to GAGs and ApoE are coordinated and how they impact TREM2 function in microglia.

Our results illustrate two distinct paths to loss-of-function in TREM2, so how might these different mechanisms result in either AD or NHD? In attempting to explain this, it is important to take into account genetics-based dosage affects (Figure 6a). In NHD, the mutations are homozygous and the TREM2 is either deleted or misfolded, leading to a complete loss of function, and more serious and early-onset neurodegenerative disease. In AD, the mutations are heterozygous and impair function (but do not completely abolish it), leading to less severe and late onset neurodegenerative disease. Under this hypothesis, it should be possible that a heterozygous NHD mutant would give increased risk for AD. Consistent with this, there have been reports of rare AD cases containing heterozygous NHD variants, including Q33X, Y38C, and T66M (Guerreiro et al., 2013b). In addition, TREM2 may function not only as a receptor but also as a signaling molecule as it can be cleaved. We have recently shown that the soluble TREM2 may be a survival signal in bone-marrow macrophages (Wu et al., 2015). Interestingly, we have observed that the absence of TREM2 in an AD mouse model prevents microglia proliferation and promotes microglia apoptosis, suggesting that soluble TREM2 could play a similar role in the CNS (Wang et al., 2015). Accordingly, soluble TREM2 can be detected in the CNS, and we have shown that some AD risk variants, but not the NHD mutant proteins are readily detected in the CSF of patients (Piccio et al., 2016). Because the AD risk variant proteins are expressed and stable enough to be soluble factors, they may retain some signaling ability and prevent more serious diseases. These hypotheses will require animal knock-in studies for full evaluation. Therefore, a comprehensive analysis of all TREM2 variants will be essential to understanding TREM2 function in both neurodegenerative diseases and other inflammatory diseases, and to design targeted therapies accordingly.

1. 1. Adams PD
   2. Afonine PV
   3. Bunkóczi G
   4. Chen VB
   5. Davis IW
   6. Echols N
   7. Headd JJ
   8. Hung LW
   9. Kapral GJ
   10. Grosse-Kunstleve RW
   11. McCoy AJ
   12. Moriarty NW
   13. Oeffner R
   14. Read RJ
   15. Richardson DC
   16. Richardson JS
   17. Terwilliger TC
   18. Zwart PH

   (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution

   Acta Crystallographica. Section D, Biological Crystallography 66:213–221.

   https://doi.org/10.1107/S0907444909052925

   • PubMed
   • Google Scholar
2. 1. Atagi Y
   2. Liu CC
   3. Painter MM
   4. Chen XF
   5. Verbeeck C
   6. Zheng H
   7. Li X
   8. Rademakers R
   9. Kang SS
   10. Xu H
   11. Younkin S
   12. Das P
   13. Fryer JD
   14. Bu G

   (2015) Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

   The Journal of Biological Chemistry 290:26043–26050.

   https://doi.org/10.1074/jbc.M115.679043

   • PubMed
   • Google Scholar
3. 1. Bailey CC
   2. DeVaux LB
   3. Farzan M

   (2015) The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E

   The Journal of Biological Chemistry 290:26033–26042.

   https://doi.org/10.1074/jbc.M115.677286

   • PubMed
   • Google Scholar
4. 1. Cady J
   2. Koval ED
   3. Benitez BA
   4. Zaidman C
   5. Jockel-Balsarotti J
   6. Allred P
   7. Baloh RH
   8. Ravits J
   9. Simpson E
   10. Appel SH
   11. Pestronk A
   12. Goate AM
   13. Miller TM
   14. Cruchaga C
   15. Harms MB

   (2014) TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis

   JAMA Neurology 71:449–453.

   https://doi.org/10.1001/jamaneurol.2013.6237

   • PubMed
   • Google Scholar
5. 1. Cannon JP
   2. O'Driscoll M
   3. Litman GW

   (2012) Specific lipid recognition is a general feature of CD300 and TREM molecules

   Immunogenetics 64:39–47.

   https://doi.org/10.1007/s00251-011-0562-4

   • PubMed
   • Google Scholar
6. 1. Chouery E
   2. Delague V
   3. Bergougnoux A
   4. Koussa S
   5. Serre JL
   6. Mégarbané A

   (2008) Mutations in TREM2 lead to pure early-onset dementia without bone cysts

   Human Mutation 29:E194–E204.

   https://doi.org/10.1002/humu.20836

   • PubMed
   • Google Scholar
7. 1. Colonna M

   (2003) DAP12 signaling: from immune cells to bone modeling and brain myelination

   Journal of Clinical Investigation 111:313–314.

   https://doi.org/10.1172/JCI17745

   • Google Scholar
8. 1. Colonna M
   2. Wang Y

   (2016) TREM2 variants: new keys to decipher Alzheimer disease pathogenesis

   Nature Reviews. Neuroscience 17:201–207.

   https://doi.org/10.1038/nrn.2016.7

   • PubMed
   • Google Scholar
9. 1. Cruchaga C
   2. Kauwe JS
   3. Harari O
   4. Jin SC
   5. Cai Y
   6. Karch CM
   7. Benitez BA
   8. Jeng AT
   9. Skorupa T
   10. Carrell D
   11. Bertelsen S
   12. Bailey M
   13. McKean D
   14. Shulman JM
   15. De Jager PL
   16. Chibnik L
   17. Bennett DA
   18. Arnold SE
   19. Harold D
   20. Sims R
   21. Gerrish A
   22. Williams J
   23. Van Deerlin VM
   24. Lee VM
   25. Shaw LM
   26. Trojanowski JQ
   27. Haines JL
   28. Mayeux R
   29. Pericak-Vance MA
   30. Farrer LA
   31. Schellenberg GD
   32. Peskind ER
   33. Galasko D
   34. Fagan AM
   35. Holtzman DM
   36. Morris JC
   37. Goate AM
   38. GERAD Consortium
   39. Alzheimer’s Disease Neuroimaging Initiative (ADNI)
   40. Alzheimer Disease Genetic Consortium (ADGC)

   (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease

   Neuron 78:256–268.

   https://doi.org/10.1016/j.neuron.2013.02.026

   • PubMed
   • Google Scholar
10. 1. Daws MR
    2. Sullam PM
    3. Niemi EC
    4. Chen TT
    5. Tchao NK
    6. Seaman WE

    (2003) Pattern recognition by TREM-2: binding of anionic ligands

    Journal of Immunology 171:594–599.

    https://doi.org/10.4049/jimmunol.171.2.594

    • PubMed
    • Google Scholar
11. 1. Emsley P
    2. Lohkamp B
    3. Scott WG
    4. Cowtan K

    (2010) Features and development of Coot

    Acta Crystallographica. Section D, Biological Crystallography 66:486–501.

    https://doi.org/10.1107/S0907444910007493

    • PubMed
    • Google Scholar
12. 1. Esko JD
    2. Stewart TE
    3. Taylor WH

    (1985) Animal cell mutants defective in glycosaminoglycan biosynthesis

    PNAS 82:3197–3201.

    https://doi.org/10.1073/pnas.82.10.3197

    • PubMed
    • Google Scholar
13. 1. Gattis JL
    2. Washington AV
    3. Chisholm MM
    4. Quigley L
    5. Szyk A
    6. McVicar DW
    7. Lubkowski J

    (2006) The structure of the extracellular domain of triggering receptor expressed on myeloid cells like transcript-1 and evidence for a naturally occurring soluble fragment

    The Journal of Biological Chemistry 281:13396–13403.

    https://doi.org/10.1074/jbc.M600489200

    • PubMed
    • Google Scholar
14. 1. Golde TE
    2. Streit WJ
    3. Chakrabarty P

    (2013) ’sAlzheimer

    Alzheimer's Research & Therapy 5:24.

    https://doi.org/10.1186/alzrt178

    • PubMed
    • Google Scholar
15. 1. Guerreiro R
    2. Bilgic B
    3. Guven G
    4. Brás J
    5. Rohrer J
    6. Lohmann E
    7. Hanagasi H
    8. Gurvit H
    9. Emre M

    (2013a) A novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family

    Neurobiology of Aging 34:2890.e1–282890.

    https://doi.org/10.1016/j.neurobiolaging.2013.06.005

    • Google Scholar
16. 1. Guerreiro R
    2. Wojtas A
    3. Bras J
    4. Carrasquillo M
    5. Rogaeva E
    6. Majounie E
    7. Cruchaga C
    8. Sassi C
    9. Kauwe JS
    10. Younkin S
    11. Hazrati L
    12. Collinge J
    13. Pocock J
    14. Lashley T
    15. Williams J
    16. Lambert JC
    17. Amouyel P
    18. Goate A
    19. Rademakers R
    20. Morgan K
    21. Powell J
    22. St George-Hyslop P
    23. Singleton A
    24. Hardy J
    25. Alzheimer Genetic Analysis Group

    (2013b) ’sTREM2 variants in Alzheimer

    New England Journal of Medicine 368:117–127.

    https://doi.org/10.1056/NEJMoa1211851

    • PubMed
    • Google Scholar
17. 1. Guerreiro RJ
    2. Lohmann E
    3. Brás JM
    4. Gibbs JR
    5. Rohrer JD
    6. Gurunlian N
    7. Dursun B
    8. Bilgic B
    9. Hanagasi H
    10. Gurvit H
    11. Emre M
    12. Singleton A
    13. Hardy J

    (2013c) Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement

    JAMA Neurology 70:78–84.

    https://doi.org/10.1001/jamaneurol.2013.579

    • PubMed
    • Google Scholar
18. 1. Hamerman JA
    2. Jarjoura JR
    3. Humphrey MB
    4. Nakamura MC
    5. Seaman WE
    6. Lanier LL

    (2006) Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12

    Journal of Immunology 177:2051–2055.

    https://doi.org/10.4049/jimmunol.177.4.2051

    • PubMed
    • Google Scholar
19. 1. Hsieh CL
    2. Koike M
    3. Spusta SC
    4. Niemi EC
    5. Yenari M
    6. Nakamura MC
    7. Seaman WE

    (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia

    Journal of Neurochemistry 109:1144–1156.

    https://doi.org/10.1111/j.1471-4159.2009.06042.x

    • PubMed
    • Google Scholar
20. Software

    1. Hubbard S
    2. Thornton J

    (1993)

    NACCESS, Computer Program

    Department of Biochemistry Molecular Biology, University College London.
21. 1. Ito H
    2. Hamerman JA

    (2012) TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells

    European Journal of Immunology 42:176–185.

    https://doi.org/10.1002/eji.201141679

    • PubMed
    • Google Scholar
22. 1. Jay TR
    2. Miller CM
    3. Cheng PJ
    4. Graham LC
    5. Bemiller S
    6. Broihier ML
    7. Xu G
    8. Margevicius D
    9. Karlo JC
    10. Sousa GL
    11. Cotleur AC
    12. Butovsky O
    13. Bekris L
    14. Staugaitis SM
    15. Leverenz JB
    16. Pimplikar SW
    17. Landreth GE
    18. Howell GR
    19. Ransohoff RM
    20. Lamb BT

    (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models

    The Journal of Experimental Medicine 212:287–295.

    https://doi.org/10.1084/jem.20142322

    • PubMed
    • Google Scholar
23. 1. Jin SC
    2. Benitez BA
    3. Karch CM
    4. Cooper B
    5. Skorupa T
    6. Carrell D
    7. Norton JB
    8. Hsu S
    9. Harari O
    10. Cai Y
    11. Bertelsen S
    12. Goate AM
    13. Cruchaga C

    (2014) ’sCoding variants in TREM2 increase risk for Alzheimer

    Human Molecular Genetics 23:5838–5846.

    https://doi.org/10.1093/hmg/ddu277

    • PubMed
    • Google Scholar
24. 1. Jonsson T
    2. Stefansson H
    3. Steinberg S
    4. Jonsdottir I
    5. Jonsson PV
    6. Snaedal J
    7. Bjornsson S
    8. Huttenlocher J
    9. Levey AI
    10. Lah JJ
    11. Rujescu D
    12. Hampel H
    13. Giegling I
    14. Andreassen OA
    15. Engedal K
    16. Ulstein I
    17. Djurovic S
    18. Ibrahim-Verbaas C
    19. Hofman A
    20. Ikram MA
    21. van Duijn CM
    22. Thorsteinsdottir U
    23. Kong A
    24. Stefansson K

    (2013) ’sVariant of TREM2 associated with the risk of Alzheimer

    New England Journal of Medicine 368:107–116.

    https://doi.org/10.1056/NEJMoa1211103

    • PubMed
    • Google Scholar
25. 1. Karplus PA
    2. Diederichs K

    (2012) Linking crystallographic model and data quality

    Science 336:1030–1033.

    https://doi.org/10.1126/science.1218231

    • PubMed
    • Google Scholar
26. 1. Kawabori M
    2. Kacimi R
    3. Kauppinen T
    4. Calosing C
    5. Kim JY
    6. Hsieh CL
    7. Nakamura MC
    8. Yenari MA

    (2015) Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke

    Journal of Neuroscience 35:3384–3396.

    https://doi.org/10.1523/JNEUROSCI.2620-14.2015

    • PubMed
    • Google Scholar
27. 1. Kelker MS
    2. Debler EW
    3. Wilson IA

    (2004a) Crystal structure of mouse triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.76 A

    Journal of Molecular Biology 344:1175–1181.

    https://doi.org/10.1016/j.jmb.2004.10.009

    • PubMed
    • Google Scholar
28. 1. Kelker MS
    2. Foss TR
    3. Peti W
    4. Teyton L
    5. Kelly JW
    6. Wüthrich K
    7. Wilson IA

    (2004b) Crystal structure of human triggering receptor expressed on myeloid cells 1 (TREM-1) at 1.47 A

    Journal of Molecular Biology 342:1237–1248.

    https://doi.org/10.1016/j.jmb.2004.07.089

    • PubMed
    • Google Scholar
29. 1. Kleinberger G
    2. Yamanishi Y
    3. Suárez-Calvet M
    4. Czirr E
    5. Lohmann E
    6. Cuyvers E
    7. Struyfs H
    8. Pettkus N
    9. Wenninger-Weinzierl A
    10. Mazaheri F
    11. Tahirovic S
    12. Lleó A
    13. Alcolea D
    14. Fortea J
    15. Willem M
    16. Lammich S
    17. Molinuevo JL
    18. Sánchez-Valle R
    19. Antonell A
    20. Ramirez A
    21. Heneka MT
    22. Sleegers K
    23. van der Zee J
    24. Martin JJ
    25. Engelborghs S
    26. Demirtas-Tatlidede A
    27. Zetterberg H
    28. Van Broeckhoven C
    29. Gurvit H
    30. Wyss-Coray T
    31. Hardy J
    32. Colonna M
    33. Haass C

    (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis

    Science Translational Medicine 6:243ra86.

    https://doi.org/10.1126/scitranslmed.3009093

    • PubMed
    • Google Scholar
30. 1. Kobayashi N
    2. Karisola P
    3. Peña-Cruz V
    4. Dorfman DM
    5. Jinushi M
    6. Umetsu SE
    7. Butte MJ
    8. Nagumo H
    9. Chernova I
    10. Zhu B
    11. Sharpe AH
    12. Ito S
    13. Dranoff G
    14. Kaplan GG
    15. Casasnovas JM
    16. Umetsu DT
    17. Dekruyff RH
    18. Freeman GJ

    (2007) TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells

    Immunity 27:927–940.

    https://doi.org/10.1016/j.immuni.2007.11.011

    • PubMed
    • Google Scholar
31. 1. Kober DL
    2. Wanhainen KM
    3. Johnson BM
    4. Randolph DT
    5. Holtzman MJ
    6. Brett TJ

    (2014) Preparation, crystallization, and preliminary crystallographic analysis of wild-type and mutant human TREM-2 ectodomains linked to neurodegenerative and inflammatory diseases

    Protein Expression and Purification 96:32–38.

    https://doi.org/10.1016/j.pep.2014.01.015

    • PubMed
    • Google Scholar
32. 1. Kober DL
    2. Yurtsever Z
    3. Brett TJ

    (2015) Efficient mammalian cell expression and Single-step purification of extracellular glycoproteins for crystallization

    Journal of Visualized Experiments 106:e53445.

    https://doi.org/10.3791/53445

    • Google Scholar
33. 1. Laskowski RA
    2. Swindells MB

    (2011) LigPlot+: multiple ligand-protein interaction diagrams for drug discovery

    Journal of Chemical Information and Modeling 51:2778–2786.

    https://doi.org/10.1021/ci200227u

    • PubMed
    • Google Scholar
34. 1. Le Ber I
    2. De Septenville A
    3. Guerreiro R
    4. Bras J
    5. Camuzat A
    6. Caroppo P
    7. Lattante S
    8. Couarch P
    9. Kabashi E
    10. Bouya-Ahmed K
    11. Dubois B
    12. Brice A

    (2014) Homozygous TREM2 mutation in a family with atypical frontotemporal dementia

    Neurobiology of Aging 35:2419.e23–2412.e25.

    https://doi.org/10.1016/j.neurobiolaging.2014.04.010

    • Google Scholar
35. 1. McDonald IK
    2. Thornton JM

    (1994) Satisfying hydrogen bonding potential in proteins

    Journal of Molecular Biology 238:777–793.

    https://doi.org/10.1006/jmbi.1994.1334

    • PubMed
    • Google Scholar
36. 1. Meyer PA
    2. Socias S
    3. Key J
    4. Ransey E
    5. Tjon EC
    6. Buschiazzo A
    7. Lei M
    8. Botka C
    9. Withrow J
    10. Neau D
    11. Rajashankar K
    12. Anderson KS
    13. Baxter RH
    14. Blacklow SC
    15. Boggon TJ
    16. Bonvin AM
    17. Borek D
    18. Brett TJ
    19. Caflisch A
    20. Chang CI
    21. Chazin WJ
    22. Corbett KD
    23. Cosgrove MS
    24. Crosson S
    25. Dhe-Paganon S
    26. Di Cera E
    27. Drennan CL
    28. Eck MJ
    29. Eichman BF
    30. Fan QR
    31. Ferré-D'Amaré AR
    32. Fromme JC
    33. Garcia KC
    34. Gaudet R
    35. Gong P
    36. Harrison SC
    37. Heldwein EE
    38. Jia Z
    39. Keenan RJ
    40. Kruse AC
    41. Kvansakul M
    42. McLellan JS
    43. Modis Y
    44. Nam Y
    45. Otwinowski Z
    46. Pai EF
    47. Pereira PJ
    48. Petosa C
    49. Raman CS
    50. Rapoport TA
    51. Roll-Mecak A
    52. Rosen MK
    53. Rudenko G
    54. Schlessinger J
    55. Schwartz TU
    56. Shamoo Y
    57. Sondermann H
    58. Tao YJ
    59. Tolia NH
    60. Tsodikov OV
    61. Westover KD
    62. Wu H
    63. Foster I
    64. Fraser JS
    65. Maia FR
    66. Gonen T
    67. Kirchhausen T
    68. Diederichs K
    69. Crosas M
    70. Sliz P

    (2016) Data publication with the structural biology data grid supports live analysis

    Nature Communications 7:10882.

    https://doi.org/10.1038/ncomms10882

    • PubMed
    • Google Scholar
37. 1. Miyanishi M
    2. Tada K
    3. Koike M
    4. Uchiyama Y
    5. Kitamura T
    6. Nagata S

    (2007) Identification of Tim4 as a phosphatidylserine receptor

    Nature 450:435–439.

    https://doi.org/10.1038/nature06307

    • PubMed
    • Google Scholar
38. 1. Morin A
    2. Eisenbraun B
    3. Key J
    4. Sanschagrin PC
    5. Timony MA
    6. Ottaviano M
    7. Sliz P

    (2013) Collaboration gets the most out of software

    eLife 2:e01456.

    https://doi.org/10.7554/eLife.01456

    • PubMed
    • Google Scholar
39. 1. Niesen FH
    2. Berglund H
    3. Vedadi M

    (2007) The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability

    Nature Protocols 2:2212–2221.

    https://doi.org/10.1038/nprot.2007.321

    • PubMed
    • Google Scholar
40. 1. Numasawa Y
    2. Yamaura C
    3. Ishihara S
    4. Shintani S
    5. Yamazaki M
    6. Tabunoki H
    7. Satoh JI

    (2011) Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family

    European Journal of Neurology 18:1179–1183.

    https://doi.org/10.1111/j.1468-1331.2010.03311.x

    • PubMed
    • Google Scholar
41. Book

    1. Otwinowski Z
    2. Minor W

    (1997)

    Processing of X-Ray Diffraction Data Collected in Oscillation Mode

    New York: Academic Press.

    • Google Scholar
42. 1. Paloneva J
    2. Mandelin J
    3. Kiialainen A
    4. Bohling T
    5. Prudlo J
    6. Hakola P
    7. Haltia M
    8. Konttinen YT
    9. Peltonen L

    (2003) DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features

    The Journal of Experimental Medicine 198:669–675.

    https://doi.org/10.1084/jem.20030027

    • PubMed
    • Google Scholar
43. 1. Paloneva J
    2. Manninen T
    3. Christman G
    4. Hovanes K
    5. Mandelin J
    6. Adolfsson R
    7. Bianchin M
    8. Bird T
    9. Miranda R
    10. Salmaggi A
    11. Tranebjaerg L
    12. Konttinen Y
    13. Peltonen L

    (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype

    American Journal of Human Genetics 71:656–662.

    https://doi.org/10.1086/342259

    • PubMed
    • Google Scholar
44. 1. Park JS
    2. Ji IJ
    3. An HJ
    4. Kang MJ
    5. Kang SW
    6. Kim DH
    7. Yoon SY

    (2015) Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus

    Traffic 16:510–518.

    https://doi.org/10.1111/tra.12264

    • PubMed
    • Google Scholar
45. 1. Phongsisay V
    2. Iizasa E
    3. Hara H
    4. Yamasaki S

    (2015) 3-O-sulfo-β-D-galactose moiety of endogenous sulfoglycolipids is a potential ligand for immunoglobulin-like receptor LMIR5

    Molecular Immunology 63:595–599.

    https://doi.org/10.1016/j.molimm.2014.07.023

    • PubMed
    • Google Scholar
46. 1. Piccio L
    2. Deming Y
    3. Del-Águila JL
    4. Ghezzi L
    5. Holtzman DM
    6. Fagan AM
    7. Fenoglio C
    8. Galimberti D
    9. Borroni B
    10. Cruchaga C

    (2016) Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status

    Acta Neuropathologica 131:925–933.

    https://doi.org/10.1007/s00401-016-1533-5

    • PubMed
    • Google Scholar
47. 1. Poliani PL
    2. Wang Y
    3. Fontana E
    4. Robinette ML
    5. Yamanishi Y
    6. Gilfillan S
    7. Colonna M

    (2015) TREM2 sustains microglial expansion during aging and response to demyelination

    The Journal of Clinical Investigation 125:2161–2170.

    https://doi.org/10.1172/JCI77983

    • PubMed
    • Google Scholar
48. 1. Quan DN
    2. Cooper MD
    3. Potter JL
    4. Roberts MH
    5. Cheng H
    6. Jarvis GA

    (2008) TREM-2 binds to lipooligosaccharides of Neisseria gonorrhoeae and is expressed on reproductive tract epithelial cells

    Mucosal Immunology 1:229–238.

    https://doi.org/10.1038/mi.2008.1

    • PubMed
    • Google Scholar
49. 1. Rayaprolu S
    2. Mullen B
    3. Baker M
    4. Lynch T
    5. Finger E
    6. Seeley WW
    7. Hatanpaa KJ
    8. Lomen-Hoerth C
    9. Kertesz A
    10. Bigio EH
    11. Lippa C
    12. Josephs KA
    13. Knopman DS
    14. White CL
    15. Caselli R
    16. Mackenzie IR
    17. Miller BL
    18. Boczarska-Jedynak M
    19. Opala G
    20. Krygowska-Wajs A
    21. Barcikowska M
    22. Younkin SG
    23. Petersen RC
    24. Ertekin-Taner N
    25. Uitti RJ
    26. Meschia JF
    27. Boylan KB
    28. Boeve BF
    29. Graff-Radford NR
    30. Wszolek ZK
    31. Dickson DW
    32. Rademakers R
    33. Ross OA

    (2013) TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease

    Molecular Neurodegeneration 8:19.

    https://doi.org/10.1186/1750-1326-8-19

    • PubMed
    • Google Scholar
50. 1. Ridge PG
    2. Hoyt KB
    3. Boehme K
    4. Mukherjee S
    5. Crane PK
    6. Haines JL
    7. Mayeux R
    8. Farrer LA
    9. Pericak-Vance MA
    10. Schellenberg GD
    11. Kauwe JSK

    (2016) Assessment of the genetic variance of late-onset alzheimer's disease

    Neurobiology of Aging 41:200.e13–200.e20.

    https://doi.org/10.1016/j.neurobiolaging.2016.02.024

    • Google Scholar
51. 1. Robert X
    2. Gouet P

    (2014) Deciphering key features in protein structures with the new ENDscript server

    Nucleic Acids Research 42:W320–W324.

    https://doi.org/10.1093/nar/gku316

    • PubMed
    • Google Scholar
52. 1. Santiago C
    2. Ballesteros A
    3. Martínez-Muñoz L
    4. Mellado M
    5. Kaplan GG
    6. Freeman GJ
    7. Casasnovas JM

    (2007) Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds

    Immunity 27:941–951.

    https://doi.org/10.1016/j.immuni.2007.11.008

    • PubMed
    • Google Scholar
53. 1. Sievers F
    2. Wilm A
    3. Dineen D
    4. Gibson TJ
    5. Karplus K
    6. Li W
    7. Lopez R
    8. McWilliam H
    9. Remmert M
    10. Söding J
    11. Thompson JD
    12. Higgins DG

    (2011) Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega

    Molecular Systems Biology 7:539.

    https://doi.org/10.1038/msb.2011.75

    • PubMed
    • Google Scholar
54. 1. Sikkink LA
    2. Ramirez-Alvarado M

    (2008) Salts enhance both protein stability and amyloid formation of an immunoglobulin light chain

    Biophysical Chemistry 135:25–31.

    https://doi.org/10.1016/j.bpc.2008.02.019

    • PubMed
    • Google Scholar
55. 1. Simhadri VR
    2. Andersen JF
    3. Calvo E
    4. Choi SC
    5. Coligan JE
    6. Borrego F

    (2012) Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells

    Blood 119:2799–2809.

    https://doi.org/10.1182/blood-2011-08-372425

    • PubMed
    • Google Scholar
56. 1. Soragna D
    2. Papi L
    3. Ratti MT
    4. Sestini R
    5. Tupler R
    6. Montalbetti L

    (2003) An italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene

    Journal of Neurology, Neurosurgery & Psychiatry 74:825–826.

    https://doi.org/10.1136/jnnp.74.6.825-a

    • PubMed
    • Google Scholar
57. 1. Stefano L
    2. Racchetti G
    3. Bianco F
    4. Passini N
    5. Gupta RS
    6. Panina Bordignon P
    7. Meldolesi J

    (2009) The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor

    Journal of Neurochemistry 110:284–294.

    https://doi.org/10.1111/j.1471-4159.2009.06130.x

    • PubMed
    • Google Scholar
58. 1. Takahashi K
    2. Rochford CD
    3. Neumann H

    (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2

    The Journal of Experimental Medicine 201:647–657.

    https://doi.org/10.1084/jem.20041611

    • PubMed
    • Google Scholar
59. 1. Takegahara N
    2. Takamatsu H
    3. Toyofuku T
    4. Tsujimura T
    5. Okuno T
    6. Yukawa K
    7. Mizui M
    8. Yamamoto M
    9. Prasad DV
    10. Suzuki K
    11. Ishii M
    12. Terai K
    13. Moriya M
    14. Nakatsuji Y
    15. Sakoda S
    16. Sato S
    17. Akira S
    18. Takeda K
    19. Inui M
    20. Takai T
    21. Ikawa M
    22. Okabe M
    23. Kumanogoh A
    24. Kikutani H

    (2006) Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis

    Nature Cell Biology 8:615–622.

    https://doi.org/10.1038/ncb1416

    • PubMed
    • Google Scholar
60. 1. Tietjen GT
    2. Gong Z
    3. Chen CH
    4. Vargas E
    5. Crooks JE
    6. Cao KD
    7. Heffern CT
    8. Henderson JM
    9. Meron M
    10. Lin B
    11. Roux B
    12. Schlossman ML
    13. Steck TL
    14. Lee KY
    15. Adams EJ

    (2014) Molecular mechanism for differential recognition of membrane phosphatidylserine by the immune regulatory receptor Tim4

    PNAS 111:E1463–E1472.

    https://doi.org/10.1073/pnas.1320174111

    • PubMed
    • Google Scholar
61. 1. Turnbull IR
    2. Gilfillan S
    3. Cella M
    4. Aoshi T
    5. Miller M
    6. Piccio L
    7. Hernandez M
    8. Colonna M

    (2006) Cutting edge: TREM-2 attenuates macrophage activation

    Journal of Immunology 177:3520–3524.

    https://doi.org/10.4049/jimmunol.177.6.3520

    • PubMed
    • Google Scholar
62. 1. Ulrich JD
    2. Finn MB
    3. Wang Y
    4. Shen A
    5. Mahan TE
    6. Jiang H
    7. Stewart FR
    8. Piccio L
    9. Colonna M
    10. Holtzman DM

    (2014) Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2

    Molecular Neurodegeneration 9:20.

    https://doi.org/10.1186/1750-1326-9-20

    • PubMed
    • Google Scholar
63. 1. Wang Y
    2. Cella M
    3. Mallinson K
    4. Ulrich JD
    5. Young KL
    6. Robinette ML
    7. Gilfillan S
    8. Krishnan GM
    9. Sudhakar S
    10. Zinselmeyer BH
    11. Holtzman DM
    12. Cirrito JR
    13. Colonna M

    (2015) ’sTREM2 lipid sensing sustains the microglial response in an Alzheimer

    Cell 160:1061–1071.

    https://doi.org/10.1016/j.cell.2015.01.049

    • PubMed
    • Google Scholar
64. 1. Wang Y
    2. Ulland TK
    3. Ulrich JD
    4. Song W
    5. Tzaferis JA
    6. Hole JT
    7. Yuan P
    8. Mahan TE
    9. Shi Y
    10. Gilfillan S
    11. Cella M
    12. Grutzendler J
    13. DeMattos RB
    14. Cirrito JR
    15. Holtzman DM
    16. Colonna M

    (2016) TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

    The Journal of Experimental Medicine 213:667–675.

    https://doi.org/10.1084/jem.20151948

    • PubMed
    • Google Scholar
65. 1. Wu K
    2. Byers DE
    3. Jin X
    4. Agapov E
    5. Alexander-Brett J
    6. Patel AC
    7. Cella M
    8. Gilfilan S
    9. Colonna M
    10. Kober DL
    11. Brett TJ
    12. Holtzman MJ

    (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection

    The Journal of Experimental Medicine 212:681–697.

    https://doi.org/10.1084/jem.20141732

    • PubMed
    • Google Scholar
66. 1. Yeh FL
    2. Wang Y
    3. Tom I
    4. Gonzalez LC
    5. Sheng M

    (2016) TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia

    Neuron 91:328–340.

    https://doi.org/10.1016/j.neuron.2016.06.015

    • PubMed
    • Google Scholar
67. 1. Yoon SH
    2. Lee YD
    3. Ha J
    4. Lee Y
    5. Kim HH

    (2012) TLT-1s, alternative transcripts of triggering receptor expressed on myeloid cell-like transcript-1 (TLT-1), Inhibits the triggering receptor expressed on myeloid cell-2 (TREM-2)-mediated signaling pathway during osteoclastogenesis

    The Journal of Biological Chemistry 287:29620–29626.

    https://doi.org/10.1074/jbc.M112.351239

    • PubMed
    • Google Scholar
68. 1. Yuan P
    2. Condello C
    3. Keene CD
    4. Wang Y
    5. Bird TD
    6. Paul SM
    7. Luo W
    8. Colonna M
    9. Baddeley D
    10. Grutzendler J

    (2016) TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy

    Neuron 90:724–739.

    https://doi.org/10.1016/j.neuron.2016.05.003

    • PubMed
    • Google Scholar
69. 1. Zhang B
    2. Gaiteri C
    3. Bodea LG
    4. Wang Z
    5. McElwee J
    6. Podtelezhnikov AA
    7. Zhang C
    8. Xie T
    9. Tran L
    10. Dobrin R
    11. Fluder E
    12. Clurman B
    13. Melquist S
    14. Narayanan M
    15. Suver C
    16. Shah H
    17. Mahajan M
    18. Gillis T
    19. Mysore J
    20. MacDonald ME
    21. Lamb JR
    22. Bennett DA
    23. Molony C
    24. Stone DJ
    25. Gudnason V
    26. Myers AJ
    27. Schadt EE
    28. Neumann H
    29. Zhu J
    30. Emilsson V

    (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease

    Cell 153:707–720.

    https://doi.org/10.1016/j.cell.2013.03.030

    • PubMed
    • Google Scholar

Author details

1. Daniel L Kober

   1. Molecular Microbiology and Microbial Pathogenesis Program, Washington University School of Medicine, St. Louis, United States
   2. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States

   Contribution

   DLK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

2. Jennifer M Alexander-Brett

   Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States

   Contribution

   JMA-B, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Celeste M Karch

   Department of Psychiatry, Washington University School of Medicine, St. Louis, United States

   Contribution

   CMK, Conception and design, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-6854-5547

4. Carlos Cruchaga

   Department of Psychiatry, Washington University School of Medicine, St. Louis, United States

   Contribution

   CC, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Marco Colonna

   Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States

   Contribution

   MC, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

6. Michael J Holtzman

   1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States
   2. Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, United States
   3. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, United States

   Contribution

   MJH, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

7. Thomas J Brett

   Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States

   Contribution

   TJB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   For correspondence

   tbrett@wustl.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-6871-6676

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