The Role of TREML2 in Alzheimer’s Disease

Abstract

Late-onset Alzheimer’s disease (AD) accounts for most of all AD casesand is currently considered a complex disorder caused by a combination of environmental and genetic factors. As an important family member of triggering receptor expressed on myeloid cells (TREM), TREM-like transcript 2 gene (TREML2) locates on human chromosome 6p21.1, a newly-identified hot zone for AD susceptibility, and encodes atransmembrane immune receptor. Emerging evidence implied a potential role of TREML2 in the susceptibility and pathogenesis of AD. Here, we review the recent literature about the association of TREML2 variants with AD risk and disease endophenotypes. Moreover, we summarize the latest findings regarding cellular localization and biological functions of TREML2 and speculate its possible role in AD pathogenesis. In addition, we discuss future research directions of TREML2 and AD.

Keywords

Alzheimer’s disease genetics microglia

INTRODUCTION

Alzheimer’s disease (AD) is the most common type of dementia in the elderly, affecting 5% of the population over 65 years [1]. Late-onset AD accounts for most of all AD cases and is considered a complex disorder caused by a combination of environmental and genetic factors [2]. To date, apolipoprotein E (APOE) is the only unequivocally established susceptibility gene for late-onset AD [3]. However, it has been estimated that the variation of APOE accounts for less than 50% of disease risk, suggesting that there are additional risk genes remaining to be uncovered [4].

As an important family member of triggering receptor expressed on myeloid cells (TREM), TREM-like transcript 2 gene (TREML2) locates on human chromosome 6p21.1 [5, 6], a newly-identified hot zone for AD susceptibility [7]. Emerging evidence suggested that TREML2 variants were closely associated with AD risk in Caucasians and Han Chinese [8, 9]. Meanwhile, the association of TREML2 variants with AD endophenotypes including cerebrospinal fluid (CSF) tau hyperphosphorylated at threonine 181 (p-tau) and total tau (t-tau) levels as well as volumes of AD-related brain structures was also reported [8 , 10–12]. As a321aa transmembrane immune receptor, TREML2 was revealed to be expressed by microglia in the central nervous system (CNS) [13]. TREML2 was upregulated by amyloid-β (Aβ) stimulation during AD progression [14, 15], and might exert a pro-inflammatory and proliferation promoting effect on microglia under disease context [14]. These implied a potential role of TREML2 in the susceptibility and pathogenesis of AD.

Here, we review the recent literature about the association of TREML2 variants with AD risk and disease endophenotypes. Moreover, we summarize the latest findings regarding cellular localization and biological functions of TREML2 and speculate its possible role in AD pathogenesis. In addition, we discuss future research directions of TREML2 and AD.

TREML2 VARIANTS AND AD RISK

Human TREML2 gene comprises 5 exons (see Fig. 1A). In 2014, Benitez and colleagues performed a meta-analysis of the whole-exome sequencing data from the Alzheimer’s Disease Genetic Consortium (ADGC), Genetic and Environmental Risk for Alzheimer’s disease (GERAD), European Alzheimer’s Disease Initiative (EADI), and the Alzheimer’s Research UK studies (including 16254 cases and 20052 control subjects) [8]. They found that the minor alleles of rs3747742, a coding missense variant located in the exon 3 of TREML2, significantly reduced the risk for ADin Caucasians (odds ratio (OR): 0.93; 95% confidence interval (CI): 0.89–0.96; p = 8.66×10^–5). Importantly, this protective effect provided by rs3747742-C was independent of the TREM2 p.R47H variant. As a coding missense variant, TREML2 rs3747742-C leads to a change of amino acids at the 144 residue (p.S144G) [8] (Table 1). According to the prediction of Mutation Taster and PolyPhen-2 software [16, 17], p.S144G amino acid change was unlikely to affect protein structure or functions. Interestingly, Carrasquillo et al. revealed that TREML2 rs3747742 is in linkage disequilibrium (LD) with an intergenic regulatory variant rs9357347 [18]. This variant is located 6.9 kb downstream from TREML2 and 19.6 kb upstream from TREM2, and its minor allele was associated with a reduced AD risk as well as increased TREM2 protein levels [18]. In view of this evidence, some researchers speculated that the association of TREML2 rs3747742 with AD risk might be attributed to its LD with functional variants that influenced the levels of nearby TREM genes, rather than directly affecting the structure or functions of TREML2 protein.

Fig. 1

A schematic diagram of human TREML2 gene and its protein product. A) Structures of human TREML2 gene. Human TREML2 locates on human chromosome 6p21.1 and comprises 5 exons. The length of each exon and the location of AD-related TREML2 variants have been indicated on this schematic diagram. B) Structures of TREML2 as well as other important TREM family members. Unlike its family member TREM2 and TREM1, TREML2 does not associate with DAP12 for signaling. Meanwhile, TREML2 does not bear immunoreceptor tyrosine-based inhibitory motifs like TREML1. Instead, TREML2 harbors a potential Src homology 3-binding motif in the cytoplasmic tail. ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motifs.

Table 1

TREML2 variants and AD risk

Study	Variant	Cohort	Case number	Control number	Comparison	OR	95% CI	p (corrected)
Benitez et al. 2014 [8]	rs3747742	ADGC + GERAD + EADI + Alzheimer’s Research UK	16254	20052	C versus T	0.93	0.89–0.96	8.66×10^–5
Zhang et al. 2016 [19]	rs3747742	A case-control cohort from East China	380	475	C versus T	1.039	0.848–1.274	0.7128
Jiang et al. 2017 [9]	rs3747742	A case-control cohort from North China	992	1358	CC versus CT+TT	0.713	0.546–0.932	3.9×10^–2

ADGC, Alzheimer’s Disease Genetic Consortium; EADI, European Alzheimer’s Disease Initiative; GERAD, Genetic and Environmental Risk for Alzheimer’s disease.

Owing to the genetic heterogeneity among different ethnic groups and populations, replication of this association in non-Caucasians was urgently needed. In Han Chinese, Zhang and colleagues tried to confirm the association of TREML2 rs3747742-C with AD risk by performing a genetic screening in 380 AD patients and 475 healthy individuals recruited from East China [19] (Table 1). However, no significant association was found (OR: 1.039; 95% CI: 0.848–1.274; p = 0.7128). Recently, Jiang and colleagues genotyped TREML2 rs3747742 in a Han Chinese cohort including 992AD patients and 1,358 healthy controls [9] (Table 1). TREML2 rs3747742-C was associated with a reduced AD risk under the recessive genetic model after Bonferroni correction (OR = 0.713; 95% CI: 0.546–0.932; Bonferroni-corrected p = 3.9×10^–2). The contradiction between these two Han Chinese studies might be attributed to the relatively small sample size in Zhang’s study, which potentially limited the statistical power. Interestingly, after stratifying genotype data according to APOE ɛ4 status, Jiang et al. revealed that the protection of rs3747742-C was more pronounced in APOE ɛ4 carriers (recessive genetic model, OR = 0.448; 95% CI: 0.262–0.765; Bonferroni-corrected p = 9×10^–3). This implied a potential influence of TREML2 and APOE interaction on AD risk.

In addition to rs3747742, another TREML2 variant rs115991880(p.S248R) was observed more frequently in controls (5 of 210) than AD cases (1 of 233) in a recent study using next-generation sequencing technology [20], but this did not reach statistical significance.

TREML2 VARIANTS AND AD ENDOPHENOTYPES

The intracellular aggregate of hyperphosphorylated tau in the brain represents a neuropathological feature of AD. Levels of p-tau in the CSF were correlated with the load of hyperphosphorylated tau in the brain. Meanwhile, elevated CSF t-tau levels were related to neuronal loss and predicted cognitive decline in AD patients. Therefore, tau levels in the CSF have emerged as a useful biomarker and acrucial endophenotype for AD. To identify the potential association between AD risk variant and CSF tau levels, Cruchaga and colleagues performed a genome-wide association study on 1,269 unrelated individuals recruited through the Knight Alzheimer’s Disease Research Center (Knight-ADRC) at Washington University, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a biomarker Consortium of Alzheimer Disease Centers coordinated by University of Washington and the University of Pennsylvania [10] (Table 2). They revealed that rs6916710, a variant located in the intron 2 of TREML2, was associated with decreased levels of t-tau (p = 8.2×10^–3; β= –0.03) and p-tau (p = 6.4×10^–3; β= –0.03). Interestingly, TREML2 rs6916710 is also in tight LD with the intergenic regulatory variant rs9357347. As aforementioned, rs9357347 influenced TREM2 protein levels while TREM2 was involved in modulation of tau pathology [21 –23]. This evidence raises the possibility that the relation of TREML2 rs6916710 with CSF t-tau and p-tau is attributed to its LD with the function variant rs9357347. Nevertheless, TREML2 rs6916710 might directly affect CSF levels by influencing TREML2 expression, since many intronic variants were not silent and might reduce mRNA stability as well as levels of gene products [24]. To explore the potential association between TREML2 rs3747742 and CSF levels of p-tau, Benitez and colleagues carried out a linear regression analysis using the same cohort [8] (Table 2). They found that rs3747742-C was associated with significantly lower p-tau levels (p = 1.4×10^–⁴; β= –0.02). Of note, this phenomenon was independent of the TREM2 p.R47H variant. Additionally, in a recent study, Song and colleagues assessed the relation of TREML2 rs3747742 with AD CSF biomarkers in 227 AD patients from ADNI dataset [11] (Table 2). They revealed that TREML2 rs3747742-C exhibited a strong association with reduced CSF t-tau levels at the baseline (p = 1.66×10^–²; β= –22.1210) and the 4-year follow-up (p = 1.15×10^–²; β= –0.3961). The association ofTREML2 rs3747742-C with lower levels of CSF t-tau and p-tau might explain part of the mechanisms by which this variant reduced AD risk.

Table 2

TREML2 variants and AD endophenotypes

Study	Variant location	Variant	AD endophenotypes	Cohort	Subject type	Sample size size	p (corrected)
Cruchaga et al. 2013 [10]	rs6916710	Intron 2	CSF t-tau	Knight-ADRC + ADNI	AD patients + healthy controls	815	8.2×10^-3
Cruchaga et al. 2013 [10]	rs6916710	Intron 2	CSF p-tau	Knight-ADRC + ADNI	AD patients + healthy controls	815	6.4×10^-3
Benitez et al. 2014 [8]	rs3747742	Exon 3	CSF p-tau	Knight-ADRC + ADNI + UW + UPenn	AD patients + healthy controls	1269	1.4×10^-4
Song et al. 2019 [11]	rs3747742	Exon 3	CSF t-tau	ADNI	AD patients	137	1.66×10^-2 (Baseline); 1.15×10^-2 (4-year follow-up)
Wang et al. 2020 [12]	rs3747742	Exon 3	hippocampal CA1 subfield volumes	ADNI	Cognitively normal elderly subjects	158	3.586×10^-3

ADNI, Alzheimer’s Disease Neuroimaging Initiative; Knight-ADRC, Knight Alzheimer’s Disease Research Center; UW, a biomarker consortium of Alzheimer disease centers coordinated by the University of Washington; UPenn, University of Pennsylvania.

Volumes of AD-related brain structures represent another important endophenotype, which is closely related to the underlying progression and neuropathology of AD. Using ADNI dataset, Wang and colleagues investigated the possible relation of TREML2 rs3747742 with volumes of AD-related brain structures including entorhinal cortex, middle temporal gyrus, parahippocampal gyrus, amygdala, and hippocampus in 158 cognitively normal elders [12] (Table 2). They revealed that TREML2 rs3747742-C was associated with a larger right hippocampal CA1 subfield volume after adjusting for age, gender, education years, APOE ɛ4 status, and intracranial volume under the recessive genetic model (Bonferroni corrected p = 3.586×10^–³). Since the hippocampal CA1 subfield is particularly susceptible to cytotoxicity, a larger volume of this region might provide better compensation for neuropathological damages during AD progression. Therefore, it seemed that the enhancement of brain reserve might also contribute to the protection of TREML2 rs3747742-C against AD risk.

STRUCTURE, LOCALIZATION, AND BIOLOGICAL FUNCTION OF TREML2

Unlike its family member TREM2 and TREM1, TREML2 does not associate with DAP12 for signaling [5, 25]. Meanwhile, TREML2 does not bear immunoreceptor tyrosine-based inhibitory motifs like TREML1 [26]. Instead, TREML2 harbors a potential Src homology 3-binding motif in the cytoplasmic tail [27] (see Fig. 1B). In the periphery, TREML2 is localized on myeloid and lymphoid cells including B cells [28], T cells [29, 30], neutrophils [31, 32], and macrophages [33, 34]. The endogenous ligands for TREML2 remain unclear. De Freitas et al. found that TREML2 specifically recognized and bound to phosphatidylserine, a major “eat me” signal that is exposed on the surface of apoptotic cells [33]. Azuma and colleagues revealed that murine B7–H3 could specifically bind to TREML2 and thus activate its downstream signaling [29], whereas other studies did not support a direct interaction between B7–H3 and TREML2 [35, 36]. In CD8 + T cells, activation of TREML2 enhanced immune response and promoted cell proliferation [30]. Meanwhile, the antigen-specific cytotoxicity of CD8 + T cells against tumor cells was also elevated [37]. Further molecular analyses indicated that regulation of granzyme B expression and NF-κB signaling pathway contributed to these TREML2-mediated actions [30]. In neutrophils, the expression of TREML2 was increased in response to inflammatory mediators [31]. Activation of TREML2 enhanced the neutrophil response to the formylated peptide FMLF, leading to the increased reactive oxygen species production, degranulation, and chemotaxis. In animal models, TREML2 activation potentiated the recruitment of neutrophils to sites of inflammation [32]. Consistent with the findings in neutrophils, TREML2 could also be upregulated in response to inflammatory stimuli in macrophage [28, 33]. Blockage of TREML2 on the macrophage surface by either specific anti-TREML2 antibody or soluble TREML2 extracellular domain attenuated the ability of macrophages to engulf apoptotic cells. On the contrary, overexpression of TREML2 increased the phagocytosis of apoptotic cells [33]. Taken together, these findings indicated that TREML2 played a crucial role in the modulation of immune functions.

THE POSSIBLE ROLE OF TREML2 IN AD PATHOGENESIS

In the brain, several lines of evidence indicated that TREML2 was mainly expressed by microglia, the resident CNS immune cell [8, 14]. In the context of AD, microglia can be activated by Aβ and plays a dual role during disease progression: on one side, activated microglia participates in the clearance of Aβ deposition through its phagocytic activity [38]. In contrast, chronic activation of microglia contributes to neurotoxicity by triggering pro-inflammatory cascades [39]. The functions of microglia can be modulated by numerous immune receptors, such as TREM family members TREM1 and TREM2 [40, 41]. As summarized in Table 3, TREM1 and TREM2 could regulate microglial phagocytic activity and pro-inflammatory response [21 , 42–46]. Additionally, TREM2 was revealed to modulate microglial proliferation [47], polarization [48], migration [49 –51], clustering [52, 53], and energy metabolism [54, 55]. As another crucial TREM family member, TREML2 expression could be upregulated by the stimulation of a pro-inflammatory cytokine interleukin-1β in primary microglia from C57BL/6 mice [8]. In support of these findings, Zheng and colleagues provided evidence that stimulation with lipopolysaccharide, a classic inducer of inflammatory, significantly increased microglial TREML2 expression [14]. In the settings of AD, the microglial expression was revealed to be elevated after oligomeric Aβ₄₂ stimulation. Meanwhile, an upregulation of TREML2 was observed in the brain of APP/PS1 miceduring disease progression, implying a possible contribution of TREML2 tothe AD pathogenesis [15]. At the functional levels, Zheng et al. revealed that knockdown of TREML2 suppressed the proliferation of microglia and decreased microglial-mediated pro-inflammatory cytokines production [14]. Based on this evidence, it seemed that TREML2 might exert pro-inflammatory and proliferation promoting effects on microglia during under AD context (Table 3).

Table 3

Cellular localization and possible functions of AD-related TREM family members

	TREM1	TREM2	TREML2
Cellular localization in the brain	microglia	microglia	microglia
Possible functions under AD context	regulates microglial phagocytosis of Aβ [42];	regulates microglial phagocytosis of Aβ [44, 45];	regulates microglial inflammatory response [14];
	regulates microglial inflammatory response [43]	regulates microglial inflammatory response [21, 46];	regulates microglial proliferation [14]
		regulates microglial proliferation [47], polarization [48], migration [49 –51] and clustering [52, 53];
		regulates microglial energy metabolism [54, 55]

FUTURE DIRECTIONS

Although TREML2 variants were associated with AD risk or disease endopheno types, these relations need to be validated in larger cohorts as well as in populations other than Caucasians and Han Chinese. Meanwhile, the precise mechanisms by which TREML2 variants influence the susceptibility as well as the endopheno types of AD are still unclear. Moreover, whether the interaction of TREML2 with other AD risk genes (such as TREM2 and APOE) plays a role in the above mechanisms is warranted to be explored by future studies.

Even though TREML2 was revealed to promote microglial proliferation and pro-inflammatory response, the precise signaling pathway by which TREML2 exerted these actions should be identified by future experiments. Moreover, the role of TREML2 in the modulation of other important microglial functions including phagocytosis and migration under disease context and whether TREML2 represents a potential therapeutic target for AD also merit further research.

It is worthy to note that the release of soluble isoform represents a typical feature of the TREM family [26]. Soluble forms of TREM1 and TREM2 in CSF and peripheral circulation are potential biomarkers for AD progression [53 , 56–62]. Therefore, it is valuable to determine whether the soluble form of TREML2 exists in the body fluid of AD patients and whether it possesses practical value in AD diagnosis or predicting disease progression in future.

Footnotes

ACKNOWLEDGMENTS

This work was supported by National Natural Science Foundation of China (81974156), “Six Talent Summit” Foundation of Jiangsu Province (2016-WSN-180), Youth Medical Talent Program of Jiangsu Province (QNRC2016068), Medical Innovation Team of Jiangsu Province (CXTDA2017030) and Nanjing Medical Science and Technology Development Foundation for Distinguished Young Scholars (JQX17008).

Authors’ disclosures available online ().

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