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.

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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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