Disease Associated Microglia Type 2 (Dam2) is a cell type relevant to neurodegenerative disease research. This page covers its role in brain function, involvement in disease processes, and significance for therapeutic strategies.
Disease-Associated Microglia Type 2 (DAM2) represents an intermediate activation state within the disease-associated microglia (DAM) continuum. DAM2 microglia are characterized by a unique transcriptional profile that bridges the transition from homeostatic microglia (DAM0/DAM1) to the fully activated DAM phenotype. This state was identified through single-cell RNA sequencing studies of Alzheimer's disease mouse models and is now recognized as a critical stage in microglial activation during neurodegeneration 1. [1]
The DAM2 stage represents a transitional state where microglia have: [2]
| Taxonomy | ID | Name / Label |
|---|---|---|
| Cell Ontology (CL) | CL:0000095 | neuron associated cell |
| Database | ID | Name | Confidence | [3]
|----------|----|------|------------| [4]
| Cell Ontology | CL:0000095 | neuron associated cell | Medium | [5]
| Cell Ontology | CL:0000129 | microglial cell | Medium | [6]
| Cell Ontology | CL:0004120 | retinal ganglion cell A1 | Medium |
DAM2 microglia express a distinct gene signature:
| Gene | Expression | Function |
|---|---|---|
| APOE | High | Lipid transport, lipidated ApoE production |
| TYROBP (DAP12) | High | Signaling adaptor, ITAM pathway |
| CST7 (Cystatin F) | High | Lysosomal cysteine protease inhibitor |
| ITGAX (CD11c) | High | Integrin, cell adhesion |
| CLECL1 | Moderate | C-type lectin receptor |
| LPL | High | Lipoprotein lipase, lipid metabolism |
| CD9 | High | Tetraspanin, membrane organization |
The progression to DAM2 follows a staged pathway:
Homeostatic (DAM0/1) → DAM1 → DAM2 → DAM1-like/DAM
↓ ↓ ↓ ↓
P2RY12+ Apoe+ Itgax+ Itgax+/-
Cx3cr1+ Tyrobp+ Cst7+ Cst7+/-
Tmem119+ Lpl+ Lpl++ Lpl+++
TREM2-dependent (typical DAM):
TREM2-independent (alternative DAM):
DAM2 microglia exhibit enhanced phagocytic capacity:
DAM2 represents a lipid-handling state:
DAM2 microglia upregulate antigen presentation machinery:
DAM2 microglia are prominently found surrounding amyloid plaques:
In tauopathy models:
The role of DAM2 remains controversial:
Neuroprotective aspects:
Pathogenic aspects:
| Strategy | Approach | Status |
|---|---|---|
| TREM2 agonism | Activate TREM2 signaling | Clinical trials (AL002, AL003) |
| CSF1R inhibition | Reduce microglial proliferation | Preclinical |
| Lipid metabolism modulation | Target LPL, APOE pathways | Investigational |
| CD11c targeting | Modulate Itgax+ cells | Preclinical |
DAM2-associated proteins as disease biomarkers:
Deczkowska A, Keren-Shaul H, Weiner A, et al. Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration. Cell. 2018. ↩︎
Gratuze M, Leyns CE, Holtzman DM. New insights into the role of TREM2 in Alzheimer's disease. Mol Neurodegener. 2018. ↩︎
Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017. ↩︎
Guo Y, Wei X, Yan H, et al. DAM in Alzheimer's disease: the role of microglial phenotypes. J Neuroinflammation. 2022. ↩︎
Wang S, Sudan R, Peng V, et al. TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways. J Exp Med. 2022. ↩︎
Zhou Y, Song WM, Andhey PS, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular states in Alzheimer's disease. Cell. 2020. ↩︎