Understanding the Link: TREM2 and Neurodegenerative Disorders

What is TREM2？

Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor predominantly found on microglia, the brain's immune cells. It plays a pivotal role in various diseases, notably emerging as a significant player in Alzheimer’s disease (AD) development. Structurally, TREM2 is a transmembrane protein exclusively expressed on microglia, featuring an extensive ectodomain that directly interacts with the surrounding environment, modulating microglial function. An important aspect is the ectodomain's processing by a disintegrin and metalloprotease, leading to the release of a soluble form, sTREM2. Recent research highlights sTREM2 as a bioactive molecule, capable of binding ligands, activating microglia, and orchestrating immune responses in the context of AD progression.

Clinical studies have unveiled a promising avenue: elevated sTREM2 levels in cerebrospinal fluid (CSF) of AD patients. Significantly, these levels positively correlate with classical CSF biomarkers, namely t-tau and p-tau. This correlation signifies sTREM2 as a dependable indicator of early-stage AD, offering valuable insights into the disease's onset. Understanding the role of TREM2, particularly sTREM2, not only sheds light on AD's pathogenesis but also holds potential for early diagnosis and targeted interventions.

The Structure of TREM2

TREM2, a cell-surface glycoprotein, exhibits a sophisticated structure comprising an immunoglobulin-like extracellular domain, a transmembrane region, and a short cytosolic tail. The single transmembrane helix of TREM2 interacts with DAP12, facilitating downstream signaling, while the abbreviated cytosolic tail halts signals lacking transduction or trafficking motifs [1]. Encoded by the TREM2 gene located on human chromosome 6p21.1 [2], the TREM2 protein encompasses an extracellular ectodomain (1−172 amino acids [aa]), a transmembrane domain (173−195 aa), and an intracellular domain (196−230 aa). These regions collectively mediate cell signaling: the ectodomain binds extracellular ligands, the intracellular domain binds intermediate signaling proteins, ensuring the completion of specific cellular events.

Of particular significance is the ectodomain of TREM2, susceptible to diverse post-translational modifications, directly influencing the environment and regulating microglial function. This susceptibility underscores the critical role of the ectodomain in TREM2's functionality [3]. Sequences homologous to those within the ectodomain of TREM2 might play pivotal roles mediated by TREM2 signaling [4]. Moreover, the ectodomain undergoes cleavage by a disintegrin and metalloproteinases (ADAM)-10 and ADAM-17, yielding soluble TREM2 (sTREM2). Simultaneously, the C-terminal fragment of TREM2 (TREM2-CTF) is cleaved by γ-secretase, forming the intracellular domain (ICD) [5].

The Biological Functions of Soluble TREM2

Soluble TREM2 (sTREM2) plays pivotal roles that go beyond merely acting as a decoy receptor, countering full-length TREM2 signaling. A groundbreaking study provided initial evidence showcasing sTREM2's efficiency in preventing macrophage apoptosis under low concentrations of colony stimulating factor 1 [7]. This research also hinted at sTREM2's role as an intracellular messenger, activating extracellular signal-regulated kinases 1/2 and mitogen-activated protein kinase 14, thereby promoting cell survival. Our own investigations in microglia underscored sTREM2's protective function against cellular apoptosis [8]. Notably, sTREM2 averted apoptosis in microglia by activating the AKT–glycogen synthase kinase 3β–β-catenin pathway, a mechanism distinct from that observed in macrophages. Additionally, sTREM2 induced inflammatory cytokine production in microglia by activating nuclear factor-κB, accompanied by morphological changes indicative of microglial activation. Importantly, these functions of sTREM2 were replicated in Trem2-deficient microglial cells and mouse models, indicating that sTREM2 operates independently of endogenous, full-length TREM2. Intriguingly, sTREM2 derived from Alzheimer's disease-associated variants, R47H and R62H (sTREM2-R47H and sTREM2-R62H), displayed diminished potency in suppressing apoptosis and triggering inflammatory responses in microglia. These findings may unveil previously unknown molecular mechanisms connecting TREM2 variants with an elevated risk of Alzheimer's disease.

The Clinical Significance of TREM2 Detection

In recent years, research on TREM2 has attracted widespread attention because of its role in neurological diseases, especially Alzheimer's disease. The significance of clinical detection of TREM2 is mainly reflected in the following aspects:

1. Diagnosis and prediction of neurological diseases: Research shows that TREM2 is related to the occurrence and development of neurological diseases such as Alzheimer's disease. By testing TREM2 levels, doctors can more accurately diagnose these diseases and even predict the risk of disease development at an early stage.
2. Research on disease mechanisms: Understanding the levels and functional status of TREM2 will help scientists further study the mechanisms of neurological diseases. This in-depth understanding provides important clues for the development of new drugs and the formulation of therapeutic strategies.
3. Monitoring the effects of drug treatment: Drug treatment for neurological diseases may affect the expression level of TREM2. Therefore, monitoring changes in TREM2 can help doctors evaluate the effect of drug treatment and guide subsequent treatment plans.
4. Genetic research and genetic counseling: Some TREM2 gene mutations are associated with the hereditary onset of neurological diseases. Genetic testing for TREM2 can help understand individual genetic risks and provide a basis for counseling on family genetic diseases.

TREM2 Signaling Pathway

Recent studies have illuminated the multifaceted biological functions of TREM2, encompassing cell maturation, proliferation, survival, phagocytosis, and inflammation regulation [9-11]. These diverse functions are orchestrated through the interaction between TREM2 and a plethora of potential ligands, including anionic molecules like Gram-positive and Gram-negative bacteria (such as Neisseria gonorrhoeae, Escherichia coli, and Staphylococcus aureus), DNA, lipoproteins, and phospholipids [12]. Noteworthy ligands like low-density lipoprotein (LDL) and apolipoproteins E (Apo E) exist physiologically in the body, whereas pathological β-amyloid oligomers (Aβ) are released due to tissue damage and cell death.

Upon binding to TREM2, these ligands initiate the formation of TREM2-DAP12/DAP10 heterodimers by interacting with adaptor proteins DNAX activation protein 12 (DAP12, also known as TYRO protein tyrosine kinase-binding protein) and DAP10 through oppositely charged residues [13]. For instance, the interaction between TREM2 and DAP12 is facilitated by a conserved positively-charged lysine in TREM2 (a.a.186) and a negatively-charged aspartic acid residue in DAP12, leading to the tyrosine phosphorylation of DAP12 within its immunoreceptor tyrosine-based activation motifs (ITAMs) by Src tyrosine kinases [14]. The ITAM region of DAP12 recruits spleen tyrosine kinase (SYK), activating downstream signaling molecules like phosphatidylinositol 3-kinase (PI3K), serine/threonine protein kinase Akt, mammalian target of rapamycin (mTOR), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). These activations culminate in cell activation, survival, and increased intracellular calcium levels [15-16]. Additionally, TREM2-DAP10 recruits PI3K, activating Akt and ERK. Moreover, TREM2 stabilizes β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway [17].

Intriguingly, TREM2 also negatively modulates toll-like receptor (TLR) signaling pathways, pivotal components of the innate immune system recognizing pathogen-associated molecular patterns. TREM2 attenuates Aβ1−42-mediated neuroinflammation by downregulating the TLR signaling pathway [18]. Hyperactive TLR4 induced by lipopolysaccharide (LPS) may counteract TREM2's anti-inflammatory effects, potentially linking Alzheimer’s disease to systemic inflammation. Additionally, the TREM2/TLR4/nuclear factor-kappa B (NF-κB) signaling pathway inhibits LPS-induced neuroinflammation by regulating microglial M1/M2 polarization [19].

Fig.2 The diagrammatic view of TREM2 signaling pathway. [20]

TREM2 Protein

Recombinant Human TREM2 Protein (C-mFc)

Click here for more TREM2

Synonym : TREM 2 TREM-2 TREM2 TREM2_HUMAN TREM2a TREM2b TREM2c Trggering receptor expressed on myeloid cells 2 Trggering receptor expressed on myeloid cells 2a Triggering receptor expressed on monocytes 2 Triggering receptor expressed on myeloid cells 2

References

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