Disease Associated Microglia (Dam) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
Disease Associated [microglia[/cell-types/[microglia[/cell-types/[microglia[/cell-types/microglia--TEMP--/cell-types)--FIX-- et al. (2017) in the 5xFAD mouse model of [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--, DAM are defined by downregulation of homeostatic microglial genes and upregulation of genes involved in lipid metabolism, phagocytosis, and innate immune activation. Remarkably, the DAM transcriptional signature is conserved across multiple neurodegenerative diseases, including [ALS[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX--, [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX--, and age-related neurodegeneration, suggesting a universal microglial response to neuronal injury.
DAM have attracted intense research interest because they express many known genetic risk factors for [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/alzheimers--TEMP--/diseases)--FIX-- — including [/entities/trem2|TREM2], APOE).
¶ Discovery and Characterization
The DAM phenotype was discovered through unbiased single-cell RNA sequencing of brain [microglia[/cell-types/[microglia[/cell-types/[microglia[/cell-types/[microglia--TEMP--/cell-types)--FIX-- identified a population of [microglia[/entities/microglia - Itgax (CD11c — integrin involved in [phagocytosis[/entities/microglia - Itgax (CD11c — integrin involved in [phagocytosis[/entities/microglia - Itgax (CD11c — integrin involved in [phagocytosis[/entities//entities/microglia - Itgax (CD11c — integrin involved in [phagocytosis[/entities//entities//entities/microglia - Itgax (CD11c — integrin involved in [phagocytosis[/entities//entities//entities//entities/microglia - Itgax (CD11c — integrin involved in [phagocytosis](/entities//entities//entities//entities/microglia - Itgax (CD11c — integrin involved in phagocytosis)
- Clec7a (Dectin-1 — pattern recognition receptor)
- Spp1 (osteopontin — extracellular matrix protein)
- Axl and Tyro3 (TAM receptor kinases — efferocytosis)
- Cd9 (tetraspanin involved in cell adhesion and migration)
- Gpnmb (glycoprotein nonmetastatic melanoma protein B)
DAM activation occurs through a stepwise process:
**Stage 1 ([TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX--
- Triggered independently of [TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX-- signaling
Stage 2 (dependent on [TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX-- signaling):
- Full activation of the DAM program requires [TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX-- signaling
- Enhanced phagocytic capacity and migration toward pathology
- [TREM2[/genes/[trem2[/genes/[trem2[/genes/[trem2--TEMP--/genes)--FIX-- is a cell-surface receptor on [microglia[/cell-types/microglia that signals through DAP12 ([TYROBP[/cell-types/microglia that signals through DAP12 ([TYROBP[/cell-types/microglia that signals through DAP12 ([TYROBP[/cell-types//cell-types/microglia that signals through DAP12 ([TYROBP[/cell-types//cell-types//cell-types/microglia that signals through DAP12 ([TYROBP[/cell-types//cell-types//cell-types//cell-types/microglia that signals through DAP12 ([TYROBP](/cell-types//cell-types//cell-types//cell-types/microglia that signals through DAP12 (TYROBP) to activate PI3K/Akt and Syk-dependent pathways (Ulland and Colonna, 2018).)
[TREM2[/entities/[trem2[/entities/[trem2[/entities/[trem2--TEMP--/entities)--FIX-- ligands include:
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Phospholipids (phosphatidylserine, phosphatidylcholine) on apoptotic [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--
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[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- oligomers and fibrils
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[APOE[/APOE/[Krasemann[/APOE/[Krasemann[/APOE/[Krasemann[/APOE/[Krasemann[/APOE/[Krasemann[/APOE/Krasemann et al. (2017)](https://pubmed.ncbi.nlm.nih.gov/28930663/) identified the TREM2-[APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX-- pathway as a key regulatory axis driving the transcriptional phenotype of dysfunctional [microglia[/entities/[microglia[/entities/[microglia[/entities/[microglia--TEMP--/entities)--FIX-- across neurodegenerative diseases:
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TREM2 activation induces [APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX--.
DAM are most extensively characterized in [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX-- models and human tissue:
- Plaque association: DAM preferentially cluster around [amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- plaques, forming a barrier that compacts plaques and limits their toxic halo (Yuan et al., 2016)
- [Amyloid] clearance: TREM2-dependent phagocytosis of amyloid fibrils and damaged myelin
- Plaque seeding: Elevating TREM2 reduces amyloid seeding and suppresses DAM in early disease stages (Dhandapani et al., 2022)
- [Tau[/entities/[tau-protein[/entities/[tau-protein[/entities/[tau-protein--TEMP--/entities)--FIX-- interaction: DAM response may promote tau propagation] through exosome release and inflammatory signaling
- Human validation: scRNA-seq of human AD brains confirms the presence of DAM-like populations, though with some species-specific differences (Zhou et al., 2020)
DAM are found in [ALS[/diseases/[als[/diseases/[als[/diseases/[als--TEMP--/diseases)--FIX-- spinal cord, particularly near degenerating motor [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--:
- [SOD1[/proteins/[sod1-protein[/proteins/[sod1-protein[/proteins/[sod1-protein--TEMP--/proteins)--FIX-- mutant mice show progressive DAM accumulation
- The DAM signature in ALS overlaps substantially with AD, suggesting a conserved response
- TREM2 deficiency accelerates disease progression in SOD1 mice
- DAM may support motor neuron survival in early disease but become dysfunctional with chronic activation
In [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX-- and related synucleinopathies:
- DAM-like microglia are found near [/proteins/alpha-synuclein|alpha-synuclein] pathology
- [LRRK2[/genes/[lrrk2[/genes/[lrrk2[/genes/[lrrk2--TEMP--/genes)--FIX-- mutations affect microglial inflammatory responses and DAM activation
- [GBA1[/genes/[gba[/genes/[gba[/genes/[gba--TEMP--/genes)--FIX-- mutations alter lipid metabolism in microglia, potentially affecting DAM function
- [substantia nigra[/brain-regions/[substantia-nigra[/brain-regions/[substantia-nigra[/brain-regions/[substantia-nigra--TEMP--/brain-regions)--FIX-- microglia show unique vulnerability profiles
DAM contribute to both pathology and repair in [multiple sclerosis[/diseases/[multiple-sclerosis[/diseases/[multiple-sclerosis[/diseases/[multiple-sclerosis--TEMP--/diseases)--FIX--:
- Active lesions show abundant DAM with phagocytic activity directed at [myelin debris]
- Efficient myelin debris clearance by DAM is required for remyelination
- Chronic active lesion rims ("smoldering plaques") contain iron-laden, dysfunctional DAM
- The EAE model shows TREM2-[APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX--
Krasemann et al. (2017) described MGnD as an [APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX--
LDAM are a recently described subset characterized by (Li et al., 2025):
- Accumulation of intracellular lipid droplets
- Impaired phagocytic capacity
- Elevated [oxidative stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- and [reactive oxygen species[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- production
- Dysregulated lipid metabolism
- Increased with aging and in neurodegenerative disease
- May represent a late-stage DAM phenotype or a distinct microglial state
- Emerging as therapeutic targets for age-related neurodegeneration
Identified by electron microscopy, dark microglia are ultrastructurally distinct cells found near amyloid plaques. They show condensed cytoplasm, nuclear chromatin, and extensive contacts with synapses. They may represent a morphological correlate of the DAM transcriptional state.
A microglial subtype characterized by upregulation of type I interferon-stimulated genes. IRM are found in aging and AD brains and may represent a parallel but distinct activation pathway from DAM, driven by the [STING[/entities/[sting-pathway[/entities/[sting-pathway[/entities/[sting-pathway--TEMP--/entities)--FIX-- pathway] and [/entities/nf-kb|NF-κB] signaling.
- Amyloid compaction: DAM form a protective barrier around [amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- plaques, limiting toxic oligomer release
- Phagocytic clearance: Enhanced phagocytosis of cellular debris, damaged myelin, and protein aggregates
- Neurotrophic support: DAM express growth factors and survival signals
- TREM2 loss-of-function worsens disease: TREM2 knockout exacerbates neurodegeneration in most models, suggesting DAM serve an essential protective role
- Synaptic protection: DAM may clear [complement system[/entities/[complement-system[/entities/[complement-system[/entities/[complement-system--TEMP--/entities)--FIX---tagged dysfunctional synapses while preserving healthy connections
- Chronic inflammation: Sustained DAM activation drives chronic [neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation[/mechanisms/[neuroinflammation--TEMP--/mechanisms)--FIX-- through cytokine release (TNF-α, IL-1β, IL-6)
- Excessive synaptic pruning: DAM-mediated complement-dependent phagocytosis of synapses may be excessive, contributing to [synaptic dysfunction[/mechanisms/[synaptic-dysfunction[/mechanisms/[synaptic-dysfunction[/mechanisms/[synaptic-dysfunction--TEMP--/mechanisms)--FIX--
- Tau propagation: DAM may facilitate tau propagation] through phagocytosis and release of tau-containing exosomes
- Oxidative damage: Activated DAM produce [reactive oxygen species[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- that damage surrounding [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--
- Loss of homeostatic functions: Downregulation of homeostatic genes means loss of normal microglial surveillance and neuron-support functions
The emerging consensus is that DAM function is context-dependent (Yin et al., 2025):
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Disease stage: DAM may be protective early (clearing pathological proteins) but become dysfunctional and neurotoxic with chronic activation
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Brain region: DAM responses vary by brain region, with different functional consequences in [brain-regions/hippocampus|hippocampus] vs. [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--
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Genetic background: [APOE/Alzheimer's) disease]:
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AL002 (Alector/AbbVie): Anti-TREM2 antibody in Phase 2 trials for early AD
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Mechanism: Enhances TREM2 signaling to promote DAM activation, phagocytosis, and amyloid clearance
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Challenges: Optimal TREM2 expression level is critical — too much or too little may be harmful (Claes et al., 2026)
- Targeting [APOE[/genes/[apoe[/genes/[apoe[/genes/[apoe--TEMP--/genes)--FIX--
- Promoting beneficial DAM functions while suppressing neurotoxic properties
- Selectively enhancing phagocytic capacity without inflammatory activation
- Temporal control of DAM activation (promote early, suppress late)
- Soluble TREM2 (sTREM2) in CSF as a biomarker of microglial activation
- PET tracers for activated microglia (TSPO ligands) to image DAM in vivo
- Blood-based biomarkers reflecting DAM state for clinical monitoring
Several transcription factors regulate the DAM program:
- Bhlhe40: Commonly induced in reactive microglia through TREM2-[APOE[/entities/[apoe[/entities/[apoe[/entities/[apoe--TEMP--/entities)--FIX-- signaling
- Tfec: Lysosomal gene regulator activated in DAM
- Atf3: Stress-response transcription factor upregulated in DAM
- SPI1 (PU.1): Master regulator of myeloid cell identity; AD risk locus that may influence DAM activation threshold
- MEF2C: Homeostatic microglial transcription factor downregulated in DAM
The study of Disease-Associated Microglia - Biomedical literature
- [Entities Index[/[entities[/[entities[/[entities[/[entities[/[entities[/entities
- [Mechanisms of Neurodegeneration[/[mechanisms[/[mechanisms[/[mechanisms[/[mechanisms[/[mechanisms[/mechanisms
- [Neurodegenerative Diseases[/[diseases[/[diseases[/[diseases[/[diseases[/[diseases[/diseases
Recent studies further refine [disease-associated microglia[/cell-types/[neuroinflammation-microglia[/cell-types/[neuroinflammation-microglia[/cell-types/[neuroinflammation-microglia--TEMP--/cell-types)--FIX-- (Nature) identifies protective state modules within [microglia[/cell-types/[microglia[/cell-types/[microglia[/cell-types/[microglia--TEMP--/cell-types)--FIX--" title="Goate et al., Lymphoid gene expression supports neuroprotective microglia function (2025)">[15]
Disease Associated Microglia (Dam) plays an important role in the study of neurodegenerative diseases. This page provides comprehensive information about this topic, including its mechanisms, significance in disease processes, and therapeutic implications.
- [Keren-Shaul, H., Spinrad, A., Weiner, A., et al. (2017). A unique microglia type associated with restricting development of [Alzheimer's disease[/diseases/[alzheimers[/diseases/[alzheimers[/diseases/[alzheimers--TEMP--/diseases)--FIX--. Cell, 169(7), 1276-1290. . . DOI
- [Krasemann, S., Madore, C., Cialic, R., et al. (2017). The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity, 47(3), 566-581. PubMed)
- [Deczkowska, A., Keren-Shaul, H., Weiner, A., et al. (2018). Disease-associated microglia: A universal immune sensor of neurodegeneration. Cell, 173(5), 1073-1081. . DOI)
- [Ulland, T. K., & Colonna, M. (2018). TREM2 — a key player in microglial biology and Alzheimer's Disease. Nature Reviews Neurology, 14(11), 667-675. . . DOI
- [Zhou, Y., Song, W. M., Andhey, P. S., et al. (2020). Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's Disease. Nature Medicine, 26(1), 131-142. . DOI)
- [Yin, Z., et al. (2025). Disease-associated microglia in neurodegenerative diseases: Friend or foe? PLoS Biology, 23(7), e3003426. . DOI)
- [Claes, C., et al. (2026). TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism. Nature Communications. . DOI)
- [Leyns, C. E. G., et al. (2025). Enhancing TREM2 expression activates microglia and modestly mitigates tau pathology and neurodegeneration. Journal of neuroinflammation. PMC)
- [Li, Y., et al. (2025). Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases. npj Aging, 11, 295. . DOI)
- [Dhandapani, R., et al. (2022). Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia. Journal of Experimental Medicine, 219(12), e20212479. . DOI)
- [Hickman, S., Izzy, S., Sen, P., Morsett, L., & El Khoury, J. (2018). [Microglia[/[DOI[/[DOI[/[DOI[/[DOI[/[DOI[/DOI](https://doi.org/10.1038/s41593-018-0242-x)
- [Hammond, T. R., Dufort, C., Bhatt, D., et al. (2019). Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity, 50(1), 253-271. . . DOI
- [Shi, Y., & Bhatt, D. (2025). Shifting microglial phenotypes: Targeting disease-associated microglia in neurodegeneration. ACS Chemical Neuroscience. . DOI)
- [Sala Frigerio, C., Wolfs, L., Fattorelli, N., et al. (2019). The major risk factors for Alzheimer's Disease: age, sex, and genes modulate the microglia response to [Aβ[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- plaques. Cell Reports, 27(4), 1293-1306. . . DOI
- Goate et al., Lymphoid gene expression supports neuroprotective microglia function (2025)
- Mullard et al., PICALM Alzheimer's risk allele causes aberrant lipid droplets in microglia (2025)
- Colonna et al., The gain-of-function TREM2-T96K mutation increases risk for Alzheimer's Disease by impairing microglial function (2026)
🔴 Low Confidence
| Dimension |
Score |
| Supporting Studies |
17 references |
| Replication |
0% |
| Effect Sizes |
0% |
| Contradicting Evidence |
0% |
| Mechanistic Completeness |
50% |
Overall Confidence: 36%