Nature Communications | TREM2 Expression Level Determines Microglial Metabolic State and Agonist Response Efficacy

By constructing a TREM2 reporter mouse model, this study reveals that TREM2 expression levels regulate microglial metabolic reprogramming and phagocytic function in a gradient-dependent manner. It further identifies that microglia with intermediate TREM2 expression exhibit the highest sensitivity to agonist antibodies, providing a crucial therapeutic window for Alzheimer’s disease immunotherapy.

 

Literature Overview

This paper, 'TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism,' published in Nature Communications, reviews and summarizes the dose-dependent role of TREM2 in microglial metabolic regulation and disease response. The research team generated a TREM2-mKate2 knock-in reporter mouse and combined single-cell sorting, transcriptomics, metabolomics, and lipidomics analyses to systematically dissect functional changes in microglia under varying TREM2 expression levels, and to evaluate differences in therapeutic responses to TREM2 agonist antibodies. The study reveals that TREM2 expression is closely associated with cellular metabolic activity, oxidative phosphorylation, and cholesterol homeostasis, and that agonist efficacy occurs within a specific expression window. This work provides critical theoretical foundations and biomarker guidance for developing TREM2-targeted immunotherapies. The study features rigorous experimental design, in-depth multi-omics integration, and high translational value.

Background Knowledge

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, characterized pathologically by β-amyloid (Aβ) plaque deposition and tau protein neurofibrillary tangles. Recent genome-wide association studies (GWAS) have indicated that microglial dysfunction plays a key role in late-onset AD (LOAD). Among these, Triggering Receptor Expressed on Myeloid cells 2 (TREM2), a critical regulatory receptor on microglia, significantly increases AD risk when functionally impaired. The TREM2 signaling pathway modulates microglial activation, metabolic reprogramming, phagocytosis, and inflammatory responses via the DAP12/SYK axis. Around Aβ plaques, TREM2-dependent microglia form protective barriers that limit the spread of toxic Aβ oligomers and promote plaque clearance. However, the dynamic changes in TREM2 signaling across different cellular states and its precise mechanisms in metabolic regulation remain incompletely understood. Although TREM2 agonist antibodies have shown potential in enhancing microglial function in preclinical models, early clinical trials (e.g., INVOKE-2) failed to meet primary endpoints, suggesting that treatment timing and cellular state may influence efficacy. Therefore, understanding how TREM2 expression levels determine microglial functional states has become a key scientific question in optimizing TREM2-targeted therapies. This study addresses this gap by establishing a TREM2 reporter mouse model to systematically map the relationship between TREM2 expression gradients and microglial metabolism and function, providing a theoretical foundation for precise immunointervention.

 

 

Research Methods and Experiments

The research team generated a Trem2-P2A-mKate2-KDEL knock-in reporter mouse, in which mKate2 fluorescence reflects TREM2 protein expression levels, enhanced by an ER retention sequence to improve stability. These reporter mice were crossed with APP/PS1 model mice to generate a disease model mimicking Aβ pathology. Microglia were isolated from the brains of 9- to 14-month-old mice and sorted via FACS into low-, medium-, and high-TREM2 expression subpopulations. Bulk RNA-seq, metabolomic, and lipidomic analyses were performed on sorted cells, with transcriptomic and metabolomic features systematically analyzed using bioinformatics methods such as GSVA, GSEA, and WGCNA. Glucose uptake capacity was assessed using [¹⁸F]FDG radiotracer experiments, and in vitro phagocytosis of pHrodo-labeled myelin was measured to evaluate functional activity. Additionally, long-term treatment with the blood-brain barrier-penetrant TREM2 agonist antibody ATV:4D9 was administered, and its regulatory effects on different TREM2-expressing subpopulations were evaluated using metabolomic and transcriptomic analyses.

Key Conclusions and Perspectives

• TREM2 expression is upregulated in a gradient manner near Aβ plaques, with high-TREM2-expressing microglia primarily enriched around plaques, and their numbers increase with disease progression
• Transcriptomic analysis shows that TREM2 expression drives microglia-specific gene modules, including oxidative phosphorylation, cholesterol metabolism, and interferon response pathways, independent of Aβ pathology status
• Metabolomic and lipidomic analyses reveal that high-TREM2-expressing microglia exhibit higher cellular energy substrates (e.g., ATP, SAM, phosphocreatine), enhanced pentose phosphate pathway activity, and reduced levels of free cholesterol and lactate, indicating a metabolic state biased toward oxidative metabolism and redox homeostasis
• Glucose uptake experiments show a positive correlation between TREM2 expression levels and microglial glucose uptake capacity, particularly enhanced under disease conditions
• Functional assays demonstrate that high-TREM2-expressing microglia exhibit stronger myelin phagocytic capacity, consistent across different AD models
• The efficacy of the TREM2 agonist antibody ATV:4D9 is dependent on TREM2 expression levels: microglia with intermediate TREM2 expression respond most strongly, showing significant upregulation of metabolic intermediates such as pFDG, lysosomal BMP, and peroxisomal PE(P); in contrast, metabolic responses are suppressed in high-TREM2-expressing cells, suggesting a feedback regulatory mechanism
• Agonist treatment did not significantly alter transcription levels of TREM2 or DAM marker genes, indicating that its effects are primarily mediated through metabolic reprogramming rather than transcriptional activation, with effects detectable up to one month post-treatment

Research Significance and Prospects

This study is the first to systematically reveal TREM2 expression level as a key determinant of microglial metabolic and functional states, establishing a direct link between TREM2 expression gradients and cellular energy metabolism, cholesterol homeostasis, and phagocytic function. These findings emphasize that TREM2 is not merely a molecular switch for microglial activation, but a central node in metabolic reprogramming, offering a new perspective on microglial heterogeneity.

More importantly, the study identifies an 'optimal response window' for TREM2 agonists—microglia with intermediate TREM2 expression are most responsive, while those with high expression show diminished responses. This may explain the failure of previous clinical trials of TREM2 agonists: if patients’ microglia are already in a high-TREM2 state, agonists may fail to further activate—or may even suppress—their function. Therefore, future clinical applications should consider the baseline TREM2 state of microglia, potentially requiring patient stratification using PET imaging or CSF biomarkers.

Furthermore, the study suggests that TREM2 agonists may improve membrane fluidity by enhancing the synthesis of PUFAs, phospholipids, and membrane components, thereby supporting greater phagocytic and lipid-clearance capacity. This opens new avenues for developing novel small-molecule metabolic modulators or combination therapies. Future studies should further explore the mechanisms regulating TREM2 expression and investigate how upstream signals or microenvironmental factors can 'prime' microglia into an optimal responsive state to maximize therapeutic efficacy.

 

 

Conclusion

This study, using a TREM2 reporter mouse model, systematically reveals the central role of TREM2 expression levels in microglial metabolic reprogramming and functional regulation. It demonstrates that TREM2 expression gradients are positively correlated with microglial glucose uptake, oxidative phosphorylation, cholesterol homeostasis, and phagocytic function—metabolic phenotypes independent of Aβ pathology. More importantly, the efficacy of TREM2 agonist antibodies is expression-level-dependent: microglia with intermediate TREM2 expression show the strongest response, while metabolic responses are suppressed in high-expressing cells, suggesting a feedback regulatory mechanism. This finding introduces a critical 'therapeutic window' concept for TREM2-targeted immunotherapy, emphasizing the need for personalized intervention based on microglial baseline states. The study not only deepens our understanding of microglial heterogeneity but also provides important theoretical foundations and biomarker guidance for precision immunotherapy in Alzheimer’s disease. Future research should focus on dynamically monitoring microglial TREM2 states in patients and developing combination therapies capable of 'resetting' cellular metabolic states to maximize the therapeutic potential of TREM2 agonists.

 

Astrid F Feiten, Kilian Dahm, Kai Schlepckow, Joachim L Schultze, and Christian Haass. TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism. Nature Communications.