sTREM2: Key Insights on Microglial Function and Alzheimer’s

Microglia, the brain’s resident immune cells, play a crucial role in maintaining neural health. Their function is regulated by various proteins, including triggering receptor expressed on myeloid cells 2 (TREM2). Genetic variants of TREM2 have been linked to an increased risk of Alzheimer’s disease (AD), making it a focal point for neurodegeneration research.

Understanding how sTREM2, the soluble form of this protein, influences microglial activity and interacts with pathological hallmarks of AD could provide valuable insights into disease mechanisms.

Normal Expression in the Brain

TREM2 is primarily expressed in microglia within the central nervous system (CNS), where it supports cellular homeostasis. Its levels vary across brain regions, with higher expression in the hippocampus and cortex compared to the cerebellum. This distribution aligns with areas particularly vulnerable to neurodegeneration, highlighting its significance in cognitive function.

TREM2 expression changes throughout life. During early brain development, it facilitates synaptic pruning to refine neural circuits. As the brain matures, expression stabilizes, supporting microglial surveillance and metabolism. In aging brains, TREM2 levels can fluctuate, sometimes increasing in response to cellular stressors. This dynamic regulation suggests that TREM2 adapts to the brain’s changing needs over time.

At the molecular level, transcriptional regulators like PU.1 and MITF modulate TREM2 expression, ensuring microglia maintain appropriate levels. Epigenetic mechanisms, including DNA methylation and histone acetylation, further refine its regulation. Disruptions in these processes can lead to abnormal TREM2 expression, which has been observed in various neurological disorders.

Role in Microglial Activity

Microglia depend on TREM2 to survey and respond to changes in the brain. This receptor influences microglial motility, enhancing their ability to migrate toward areas of cellular debris or distress. TREM2-deficient mouse models show impaired microglial movement, limiting their ability to maintain neural homeostasis. In disease states, this failure to reposition around degenerative regions exacerbates tissue damage.

Beyond movement, TREM2 regulates cellular metabolism, ensuring microglia have the energy necessary for their functions. Single-cell transcriptomic analyses reveal that TREM2-deficient microglia exhibit reduced oxidative phosphorylation and impaired lipid metabolism, compromising their ability to sustain surveillance and repair activities. Given microglia’s need for metabolic flexibility, TREM2’s role in energy regulation is essential.

TREM2 also influences microglial proliferation and survival. In vivo imaging and histological studies indicate that microglia lacking functional TREM2 undergo premature apoptosis, reducing their population density. This weakens the brain’s ability to respond to damage, accelerating neurodegeneration. Conversely, upregulated TREM2 supports microglial survival, reinforcing the importance of this receptor in maintaining a stable immune cell population.

Biochemical Processing of the Protein

TREM2 undergoes biochemical modifications that govern its stability, localization, and function. Initially synthesized in the endoplasmic reticulum, the protein undergoes glycosylation, a post-translational modification crucial for proper folding and trafficking. This process stabilizes TREM2’s extracellular domain and influences its interactions with membrane-associated proteins. Defects in glycosylation have been linked to pathogenic TREM2 variants associated with neurodegeneration.

Once folded, TREM2 is transported to the plasma membrane, where it anchors via its transmembrane domain. Here, it interacts with its co-receptor, DNAX-activating protein 12 (DAP12), forming a signaling complex that facilitates downstream responses. Mutations disrupting TREM2-DAP12 binding reduce surface expression and impair signaling. Lipid microdomains within the membrane influence TREM2 clustering, affecting its ability to engage extracellular ligands.

A critical aspect of TREM2 processing is its proteolytic cleavage, which generates soluble TREM2 (sTREM2). This cleavage, mediated by metalloproteases such as ADAM10 and ADAM17, is influenced by cellular stress and metabolic conditions. Increased shedding of sTREM2 occurs in response to inflammatory stimuli, suggesting dynamic regulation. Once released, sTREM2 retains ligand-binding capabilities, though its functional properties differ from the membrane-bound form.

Association With Beta-Amyloid and Tau

TREM2 modulates the accumulation and toxicity of beta-amyloid (Aβ) and tau, key pathological hallmarks of Alzheimer’s disease. Genetic studies link TREM2 variants to increased Alzheimer’s risk, with carriers exhibiting elevated Aβ deposition and tau pathology in postmortem brain analyses. These findings suggest that TREM2 function influences neurodegeneration.

Mechanistic studies show that TREM2 affects Aβ dynamics by regulating aggregation and clearance. In experimental models, TREM2 deficiency results in larger, more compact amyloid plaques, suggesting impaired plaque regulation. Enhanced TREM2 signaling, however, increases Aβ uptake, reducing extracellular accumulation. This interaction appears mediated through TREM2’s lipid-binding properties, which facilitate Aβ recognition. Disruptions in this binding capacity impair Aβ metabolism, worsening plaque burden.

Relevance in Cerebrospinal Fluid

Soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) has emerged as a potential biomarker for neurodegenerative diseases, particularly Alzheimer’s. As microglia respond to pathological changes, TREM2 shedding into CSF reflects altered microglial activity. Longitudinal studies show that sTREM2 levels rise in early Alzheimer’s stages, suggesting a compensatory microglial response to Aβ and tau pathology. However, levels often decline as the disease progresses, potentially indicating microglial dysfunction.

Beyond Alzheimer’s, sTREM2 variations have been detected in frontotemporal dementia and multiple sclerosis. The specificity of these changes remains under investigation, as distinguishing disease-related microglial activation from general neuroinflammation is complex. Advanced proteomic analyses aim to refine sTREM2’s diagnostic utility, with some research suggesting that its ratio to other CSF biomarkers, such as phosphorylated tau (p-tau) or neurofilament light chain (NfL), could improve diagnostic accuracy. Understanding sTREM2’s correlation with disease progression may aid in developing therapies that modulate microglial activity.

Analytical Techniques for Detection

Measuring sTREM2 in cerebrospinal fluid requires highly sensitive and specific analytical techniques. Enzyme-linked immunosorbent assays (ELISA) are commonly used for quantification, offering a simple and high-throughput approach. These assays rely on antibodies that selectively bind sTREM2, allowing detection at nanomolar concentrations. However, variability in antibody specificity and lot-to-lot inconsistencies can affect reproducibility, requiring rigorous validation. To improve precision, researchers have optimized ELISA protocols by incorporating monoclonal antibodies targeting distinct sTREM2 epitopes.

Mass spectrometry-based methods, such as liquid chromatography-tandem mass spectrometry (LC-MS/MS), offer enhanced specificity. Unlike immunoassays, LC-MS/MS allows direct peptide identification and quantification, reducing cross-reactivity risks. This technique has been particularly useful in distinguishing TREM2 isoforms and identifying post-translational modifications that influence function. While LC-MS/MS provides superior accuracy, its complexity and cost limit widespread clinical use. Efforts are underway to refine high-throughput workflows that combine mass spectrometry with immunoaffinity enrichment, balancing sensitivity and practicality in biomarker research.