TREM2-Related Microglial Dynamics in Neurodegenerative Diseases
Summary
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that orchestrates innate immune responses in the central nervous system. Genetic variants in TREM2 markedly increase the risk of Alzheimer’s disease and other neurodegenerative disorders by altering microglial survival, phagocytosis and cytokine release through its signalling adaptor DAP12. Proteolytic shedding of TREM2 generates a soluble fragment (sTREM2) detectable in cerebrospinal fluid, reflecting dynamic changes in microglial activation and cross-talk with neurons. Emerging research has revealed how TREM2-dependent pathways regulate microglial metabolic states, shape responses to amyloid and tau pathology, and support tissue repair. Insights into these mechanisms provide a framework for immunomodulatory therapies aimed at restoring microglial homeostasis, reducing neuroinflammation and enhancing neuronal resilience across a spectrum of proteinopathies.
Research from Nature Portfolio
Recent studies have demonstrated that engineering a high-affinity TREM2-activating antibody with a transferrin receptor binding module enables efficient blood–brain barrier transcytosis and markedly enhances microglial metabolism and proliferation in Alzheimer’s disease models. Single-cell transcriptomic analysis revealed that this strategy shifts microglia into distinct metabolically responsive states, boosting glucose uptake and promoting amyloid clearance. Complementary work uncovered that the proteolytically shed fragment, sTREM2, binds neuronal transgelin-2 to inhibit the RhoA-ROCK-GSK3β pathway, thereby reducing tau phosphorylation and ameliorating cognitive deficits in tauopathy models. Administration of an active peptide derived from sTREM2 recapitulates these protective effects, illustrating a precise microglia–neuron communication mechanism.
TREM2-Related Microglial Dynamics in Neurodegenerative Diseases publication trend
The graph below shows the total number of articles in trem2-related microglial dynamics in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).
Technical terms
TREM2: A receptor on microglia that regulates immune signalling, phagocytosis and cell survival through its adaptor protein DAP12.
Microglia: Resident immune cells of the central nervous system responsible for immune surveillance, debris clearance and modulation of neuronal function.
sTREM2: The soluble ectodomain of TREM2 released by proteolytic cleavage, serving as both a biomarker of microglial activation and a modulator of intercellular signalling.
Phagocytosis: The process by which microglia engulf and degrade cellular debris, apoptotic cells and protein aggregates to maintain tissue homeostasis.
Blood–brain barrier transcytosis: Receptor-mediated transport of molecules across the blood–brain barrier via coordinated endocytosis and exocytosis.
DAP12: A signalling adaptor protein that associates with TREM2 to relay activation signals and modulate downstream immune responses.
References
- A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models. Nature Neuroscience (2023).
- Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease. Molecular Neurodegeneration (2024).
- Soluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease. Nature Communications (2023).
- sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early‐stage Alzheimer's disease and associate with neuronal injury markers. EMBO Molecular Medicine (2016).
- TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron (2018).
- Sequential Proteolytic Processing of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Protein by Ectodomain Shedding and γ-Secretase-dependent Intramembranous Cleavage*. Journal of Biological Chemistry (2013).
- TREM2 in Neurodegenerative Diseases. Molecular Neurodegeneration (2017).
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