[TREM2](/proteins/trem2)-expressing microglia represent a specialized population of brain immune cells that play a critical role in [Alzheimer's disease](/diseases/alzheimers-disease) and other neurodegenerative conditions. These cells express the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), which is essential for microglial survival, phagocytosis, and inflammatory responses. [@guerreiro2013]
Overview
TREM2-expressing microglia are a subset of microglia that express the TREM2 receptor on their surface. TREM2 is a cell surface receptor belonging to the immunoglobulin superfamily that is expressed exclusively on myeloid cells including microglia in the brain. [@jonsson2013]
The TREM2 pathway has become one of the most important therapeutic targets in Alzheimer's disease: [@kerenshaul2017]
[TREM2](/proteins/trem2)-expressing microglia represent a specialized population of brain immune cells that play a critical role in [Alzheimer's disease](/diseases/alzheimers-disease) and other neurodegenerative conditions. These cells express the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), which is essential for microglial survival, phagocytosis, and inflammatory responses. [@guerreiro2013]
Overview
TREM2-expressing microglia are a subset of microglia that express the TREM2 receptor on their surface. TREM2 is a cell surface receptor belonging to the immunoglobulin superfamily that is expressed exclusively on myeloid cells including microglia in the brain. [@jonsson2013]
The TREM2 pathway has become one of the most important therapeutic targets in Alzheimer's disease: [@kerenshaul2017]
TREM2 variants increase AD risk by 3-4 fold
TREM2 is required for amyloid plaque clearance
TREM2 dysfunction leads to neuroinflammation
TREM2 agonists are in clinical development
Morphology and Markers
Cell Type: Activated microglia
Marker Genes: TREM2, CD33, CX3CR1, IBA1 (AIF1)
Neurotransmitter: Not applicable (immune cells)
Morphology: Amoeboid shape with multiple branching processes, enlarged soma in disease states
Location: Throughout brain parenchyma, enriched around amyloid plaques
Bone cysts: Polycystic lipomembranous osteodysplasia
Disease-Associated Microglia (DAM)
TREM2-expressing microglia transition to a DAM state in neurodegeneration:
Stage 1 DAM
Triggered by: TREM2 activation
Features: Upregulated phagocytic genes
Function: Attempted amyloid clearance
Stage 2 DAM
Triggered by: Prolonged disease stress
Features: Pro-inflammatory phenotype
Function: May become dysfunctional
Dysfunctional TREM2 Microglia
Reduced phagocytosis: Impaired amyloid clearance
Enhanced inflammation: Excessive cytokine release
Metabolic stress: Energy depletion
Neurotoxicity: May contribute to neuronal loss
Therapeutic Implications
TREM2 Agonists
Purpose: Enhance microglial function
Examples: AL002, AZD8329
Status: Clinical trials in AD
TREM2 Antagonists
Purpose: Reduce excessive inflammation
Potential: May help if overactivated
APOE Modulation
Rationale: APOE is a TREM2 ligand
Approach: APOE-targeting therapies
Biomarkers
Genetic Testing
TREM2 variants: R47H, R62H increase risk
Genetic counseling: For at-risk individuals
Fluid Biomarkers
sTREM2: Soluble TREM2 in CSF
Levels: Changes in AD progression
Imaging
PET: TSPO shows microglial activation
MRI: Structural changes associated with inflammation
Research Methods
Models
TREM2 knockouts: Mouse models for study
iPSC models: Human microglia from patients
Single-cell RNAseq: Profiling TREM2+ cells
Experimental Approaches
CRISPR: Gene editing of TREM2
Antibodies: TREM2-targeting therapeutics
Flow cytometry: Isolating TREM2+ cells
Background
The study of Trem2 Expressing [Microglia](/cell-types/microglia-neuroinflammation) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.