<table class="infobox infobox-cell">
<tr>
<th class="infobox-header" colspan="2">Disease-Associated Microglia</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>
</table>
Disease Associated Microglia 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.
<table class="infobox infobox-cell">
<tr>
<th class="infobox-header" colspan="2">Disease-Associated Microglia</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>
</table>
Disease Associated Microglia 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 (DAM) represent a distinct microglial activation state that emerges in response to chronic neurodegeneration. First identified in mouse models of Alzheimer's disease (AD), DAM are characterized by a unique transcriptional signature that distinguishes them from classical inflammatory microglia ([Keren-Shaul et al., 2017](https://doi.org/10.1016/j.cell.2017.05.018); [Krasemann et al., 2017](https://doi.org/10.1016/j.neuron.2017.09.021)). DAM adopt a specialized phenotype that combines features of both beneficial and harmful microglial activation, with functions ranging from amyloid-beta clearance to neurotoxic inflammation. Understanding DAM biology is crucial for developing microglia-targeted therapies in neurodegenerative diseases including AD, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).
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DAM were originally discovered through single-cell RNA sequencing of brain immune cells from 5xFAD mice, a well-characterized AD mouse model. Keren-Shaul et al. (2017) identified a microglial population that upregulated a cluster of genes including Apoe, Tyrobp, Cst7, Itaxk, and Hexb, while downregulating homeostatic microglial markers such as P2ry12 and Cx3cr1. This transcriptional shift occurred in a stage-dependent manner, with an initial "pre-DAM" state preceding full DAM activation.
Subsequent studies confirmed that DAM-like states exist in human neurodegenerative diseases. Single-nucleus RNA sequencing of AD patient brains revealed microglial populations expressing orthologous DAM markers (APOE, TYROBP, CST3, ITGAX) ([Grange et al., 2019](https://doi.org/10.1038/s41586-019-1195-2)). However, human DAM exhibit additional complexity, including expression of disease-specific genes not observed in mouse models.
The transition from homeostatic microglia to DAM occurs in two stages. Stage 1 pre-DAM upregulate Apoe and Tyrobp while retaining expression of homeostatic markers (P2ry12, Cx3cr1). This transitional state appears to be triggered by sensing of amyloid-beta or other disease-associated molecules through pattern recognition receptors.
Full DAM are characterized by:
DAM formation critically depends on triggering receptor expressed on myeloid cells 2 (TREM2). TREM2 is a lipid-sensing receptor expressed on microglia that recognizes amyloid-beta, apoptotic cells, and lipid-containing debris ([Wang et al., 2016](https://doi.org/10.1016/j.cell.2015.12.057)). TREM2 loss-of-function variants increase AD risk, and Trem2-deficient mice fail to form proper DAM, resulting in increased amyloid deposition ([Griciuc et al., 2013](https://doi.org/10.1016/j.neuron.2013.04.014)).
DAM may play protective roles in early disease stages:
In later disease stages, DAM become neurotoxic:
In AD, DAM accumulate around amyloid plaques, where they attempt to contain amyloid deposition while contributing to local neuroinflammation. The balance between beneficial and harmful DAM functions appears to shift with disease progression, with early stages showing protective responses and later stages exhibiting detrimental chronic inflammation ([Heneka et al., 2015](https://doi.org/10.1016/j.jneumeth.2014.11.008)). Therapeutic strategies targeting TREM2 signaling aim to enhance beneficial DAM functions while suppressing harmful inflammation.
DAM-like microglial activation occurs in PD models and patient brains, characterized by similar transcriptional changes including APOE, TYROBP, and CST7 upregulation ([Gosselin et al., 2017](https://doi.org/10.1016/j.cell.2017.10.027)). DAM in PD likely contribute to dopaminergic neuron loss through chronic neuroinflammation and may participate in alpha-synuclein propagation.
Modulating DAM represents a promising therapeutic approach:
The study of Disease Associated Microglia 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.
Recent research advances have significantly expanded our understanding of DAM biology:
The following diagram shows the key molecular relationships involving Disease-Associated Microglia discovered through SciDEX knowledge graph analysis: