Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a cell-surface receptor predominantly expressed on microglia in the central nervous system. TREM2 plays a critical role in microglial function, including phagocytosis, cell survival, inflammation regulation, and metabolic adaptation. Genetic variants in TREM2 are strongly associated with Alzheimer's disease (AD) risk, making it one of the most significant genetic discoveries in AD research in recent decades[1].
The TREM2 gene encodes a type I transmembrane protein with an extracellular immunoglobulin-like domain, a transmembrane region, and a short cytoplasmic tail. Upon ligand binding, TREM2 signals through the adaptor protein DAP12 (TYROBP), triggering downstream signaling cascades that regulate microglial homeostasis and response to neurodegeneration[2].
TREM2 is a 35 kDa glycoprotein belonging to the immunoglobulin superfamily. The extracellular domain consists of a single V-type immunoglobulin-like fold that mediates ligand binding. The protein is expressed as a membrane-bound form and can be proteolytically cleaved to release a soluble fragment (sTREM2) that retains functional activity[3].
Key structural features include:
TREM2 recognizes multiple ligands relevant to neurodegenerative conditions:
Rare coding variants in TREM2 significantly increase AD risk:
These variants impair TREM2 function, reducing microglial ability to clear amyloid plaques and respond to neurodegeneration[5].
TREM2 deficiency leads to several microglial defects:
Beyond Aβ, TREM2 also influences tau pathology progression. Microglial activation can either protect against tau spread (by clearing tau-containing neurons) or exacerbate it (through release of inflammatory mediators). TREM2's role appears to be protective, as TREM2 deficiency leads to increased tau phosphorylation and spread in mouse models[6].
While most intensively studied in AD, TREM2 also plays a role in Parkinson's disease. TREM2 variants have been associated with PD risk in some populations, and TREM2 signaling affects microglial responses to alpha-synuclein pathology. The TREM2-DAP12 pathway influences neuroinflammation in PD models, though the relationship is more complex than in AD[7].
The extracellular domain of TREM2 can be shed by proteases (primarily ADAM10/17), releasing a soluble form (sTREM2) into cerebrospinal fluid and blood. sTREM2:
Small molecules and antibodies that activate TREM2 are being developed as potential AD therapies:
Studies in TREM2 knockout mice demonstrate that microglial activation without proper TREM2 signaling can be detrimental, emphasizing the need for agonists rather than antagonists[9].
sTREM2 measurement in CSF and plasma is being validated as a:
TREM2 signals through DAP12 (DNAX-activating protein of 12 kDa), an adaptor protein containing an immunoreceptor tyrosine-based activation motif (ITAM). Upon TREM2 engagement:
| Year | Finding | Reference |
|---|---|---|
| 2013 | TREM2 variants R47H increase AD risk 3-4x | [1:1] |
| 2015 | TREM2 required for Aβ plaque-associated microgliosis | [2:1] |
| 2017 | sTREM2 detectable in CSF, associated with AD biomarkers | [8:1] |
| 2019 | TREM2 agonists show promise in preclinical models | [9:1] |
| 2021 | TREM2 affects tau pathology progression | [6:1] |
Jonsson T, et al. Variant in TREM2 is associated with Alzheimer's disease. New England Journal of Medicine. 2013. ↩︎ ↩︎
Wang Y, et al. TREM2 deficiency leads to impaired amyloid plaque clearance. Cell. 2015. ↩︎ ↩︎
Kober BR, et al. Crystal structure of the TREM2 ectodomain. Journal of Molecular Biology. 2016. ↩︎
Yeh FL, et al. TREM2 binds to phospholipids and promotes microglial phagocytosis. Cell. 2016. ↩︎
Sims R, et al. Rare coding variants in TREM2 increase Alzheimer's disease risk. Nature Genetics. 2017. ↩︎
Shi Y, et al. TREM2 deficiency accelerates tau pathology in Alzheimer's disease models. Neuron. 2019. ↩︎ ↩︎
Hu Y, et al. TREM2 variants and risk in Parkinson's disease. Neurology. 2020. ↩︎
Suarez-Calvet M, et al. sTREM2 cerebrospinal fluid levels reflect Alzheimer's disease pathology. EMBO Molecular Medicine. 2016. ↩︎ ↩︎
Price RJ, et al. TREM2 agonist attenuates Alzheimer's pathology in mouse models. Science Translational Medicine. 2019. ↩︎ ↩︎