Disease-Associated Microglia Type 2 (DAM2)

Disease-Associated Microglia Type 2 (DAM2)

Introduction

<table class="infobox infobox-cell">
<tr>
<th class="infobox-header" colspan="2">Disease-Associated Microglia Type 2 (DAM2)</th>
</tr>
<tr>
<td class="label">Taxonomy</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology (CL)</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Database</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000129](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000129)</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0004120](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0004120)</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Expression</td>
</tr>
<tr>
<td class="label">APOE</td>
<td>High</td>
</tr>
<tr>
<td class="label">TYROBP (DAP12)</td>
<td>High</td>
</tr>
<tr>
<td class="label">CST7 (Cystatin F)</td>
<td>High</td>
</tr>
<tr>
<td class="label">ITGAX (CD11c)</td>
<td>High</td>
</tr>
<tr>
<td class="label">CLECL1</td>
<td>Moderate</td>
</tr>
<tr>
<td class="labe

Disease-Associated Microglia Type 2 (DAM2)

Introduction

<table class="infobox infobox-cell">
<tr>
<th class="infobox-header" colspan="2">Disease-Associated Microglia Type 2 (DAM2)</th>
</tr>
<tr>
<td class="label">Taxonomy</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology (CL)</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Database</td>
<td>ID</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0000129](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000129)</td>
</tr>
<tr>
<td class="label">Cell Ontology</td>
<td>[CL:0004120](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0004120)</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Expression</td>
</tr>
<tr>
<td class="label">APOE</td>
<td>High</td>
</tr>
<tr>
<td class="label">TYROBP (DAP12)</td>
<td>High</td>
</tr>
<tr>
<td class="label">CST7 (Cystatin F)</td>
<td>High</td>
</tr>
<tr>
<td class="label">ITGAX (CD11c)</td>
<td>High</td>
</tr>
<tr>
<td class="label">CLECL1</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">LPL</td>
<td>High</td>
</tr>
<tr>
<td class="label">CD9</td>
<td>High</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">TREM2 agonism</td>
<td>Activate TREM2 signaling</td>
</tr>
<tr>
<td class="label">CSF1R inhibition</td>
<td>Reduce microglial proliferation</td>
</tr>
<tr>
<td class="label">Lipid metabolism modulation</td>
<td>Target LPL, APOE pathways</td>
</tr>
<tr>
<td class="label">CD11c targeting</td>
<td>Modulate Itgax+ cells</td>
</tr>
</table>

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.

Overview

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](https://pubmed.ncbi.nlm.nih.gov/27211357/). [@deczkowska2018]

The DAM2 stage represents a transitional state where microglia have: [@gratuze2018]

• Lost homeostatic markers: Downregulation of P2ry12, Cx3cr1, Tmem119
• Gained DAM markers: Upregulation of Apoe, Tyrobp, Cst7
• Acquired disease features: Phagocytic activity, lipid metabolism changes
• Maintained intermediate phenotype: Not yet fully activated DAM

<!-- multi-taxonomy-enrichment -->

Multi-Taxonomy Classification

Taxonomy Database Cross-References

Morphology & Electrophysiology

• Morphology: neuron associated cell (source: Cell Ontology)
• Morphology can be inferred from Cell Ontology classification

PanglaoDB Marker Cross-References

• Unknown (PanglaoDB):

External Database Links

• [Cell Ontology (CL:0000095)](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)
• [OBO Foundry (CL:0000095)](http://purl.obolibrary.org/obo/CL_0000095)
• [Allen Brain Cell Atlas](https://portal.brain-map.org/atlases-and-data/bkp/abc-atlas)
• [CellxGene Census](https://cellxgene.cziscience.com/)
• [Human Cell Atlas](https://www.humancellatlas.org/)
• [PanglaoDB](https://panglaodb.se/)

Taxonomy & Classification

PanglaoDB Marker Cross-References

• Unknown (PanglaoDB):

External Database Links

• [Cell Ontology (CL:0000095)](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)
• [OBO Foundry (CL:0000095)](http://purl.obolibrary.org/obo/CL_0000095)
• [Allen Brain Cell Atlas](https://portal.brain-map.org/atlases-and-data/bkp/abc-atlas)
• [CellxGene Census](https://cellxgene.cziscience.com/)
• [PanglaoDB](https://panglaodb.se/)

Molecular Signature

Transcriptomic Profile

DAM2 microglia express a distinct gene signature:

Surface Markers

• CD11c (ITGAX): Hallmark marker of DAM2
• CD9: Tetraspanin surface protein
• MHC-II: Elevated antigen presentation
• TREM2: Critical for DAM progression (when present)

Pathway to DAM2 Activation

Two-Step Activation Model

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 and Independent Pathways

TREM2-dependent (typical DAM):

• Requires TREM2 signaling for full activation
• Found in AD, other neurodegenerative conditions
• Associated with APOE-lipoprotein interaction

• Compensatory activation without TREM2
• Observed in TREM2 knockout conditions
• May represent different disease contexts

Functions

Phagocytic Activity

DAM2 microglia exhibit enhanced phagocytic capacity:

• Aβ uptake: Efficient clearance of amyloid-beta plaques
• Synaptic pruning: Increased complement-mediated synapse elimination
• Cell debris removal: Engulfment of dead neurons
• Myelin phagocytosis: Observed in demyelinating conditions

Lipid Metabolism

DAM2 represents a lipid-handling state:

• Cholesterol efflux: Upregulation of cholesterol transport genes
• Lipid droplet formation: Accumulation of lipid droplets observed
• Fatty acid oxidation: Increased β-oxidation pathways
• ApoE production: Major producer of lipidated ApoE in the brain

Antigen Presentation

DAM2 microglia upregulate antigen presentation machinery:

• MHC-II expression: Enhanced antigen presentation to CD4+ T-cells
• Co-stimulatory molecules: CD80, CD86 upregulation
• T-cell activation: Can activate adaptive immune responses

Role in Alzheimer's Disease

Plaque-Associated Microglia

DAM2 microglia are prominently found surrounding amyloid plaques:

• Plaque border localization: Concentrated at the edges of plaques
• Plaque compaction: May contribute to plaque containment
• Clearance activity: Attempted Aβ phagocytosis
• Cytokine milieu: Produce both pro- and anti-inflammatory cytokines

Tau Pathology

In tauopathy models:

• Tau uptake: Internalization of pathological tau
• Tau propagation: Potential role in spreading tau pathology
• Neuronal support: May attempt to protect tau-laden neurons

Neuroprotective vs. Pathogenic Role

The role of DAM2 remains controversial:

Neuroprotective aspects:

• Aβ clearance may reduce plaque burden
• Lipid metabolism supports neuronal health
• Trophic factor secretion

• Excessive synaptic pruning may cause connectivity loss
• Chronic inflammation contributes to progression
• May represent failed clearance attempts

Therapeutic Targeting

Modulating DAM2 Activation

Biomarker Potential

DAM2-associated proteins as disease biomarkers:

• sTREM2: Soluble TREM2 fragment, correlates with DAM activation
• APOE: Levels in CSF/ plasma reflect microglial activation
• YKL-40 (CHI3L1): Chitinase-like protein, inflammation marker

See Also

• [Microglia](/cell-types/microglia)
• [M1 Polarized Microglia](/cell-types/m1-microglia)
• [M2 Polarized Microglia](/cell-types/microglia)
• [Disease-Associated Microglia (DAM)microglia)
• [TREM2 Signaling](/diseases/m1-polarized-microglia](/diseases)
• [Neuroinflammation](/mechanisms/neuroinflammation-pathway)
• [Alzheimer's Disease Mechanisms](/mechanisms/alzheimers-disease-mechanisms)