Disease-Associated Microglia

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Introduction

Disease-Associated Microglia
Taxonomy ID
Cell Ontology (CL) [CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)
Database ID
Cell Ontology [CL:0000095](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000095)
Cell Ontology [CL:0000129](https://www.ebi.ac.uk/ols4/ontologies/cl/classes/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FCL_0000129)

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.

Overview

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; Krasemann et al., 2017). 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).

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):

Taxonomy & Classification

PanglaoDB Marker Cross-References

  • Unknown (PanglaoDB):

Discovery and Characterization

Initial Identification

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.

Evolutionary Conservation

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). However, human DAM exhibit additional complexity, including expression of disease-specific genes not observed in mouse models.

Molecular Signature

Stage 1: Pre-DAM

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.

Stage 2: Full DAM

Full DAM are characterized by:

  • Upregulated genes: Apoe, Tyrobp, Cst7, Itaxk, Hexb, Trem2, Clec7a, Cd63, Lpl, Ctsb, Ctsd

  • Downregulated genes: P2ry12, Cx3cr1, Tmem119, Selplg, Hexa

  • Functional changes: Enhanced phagocytic capacity, altered lipid metabolism, inflammatory cytokine production

TREM2 Dependency

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). 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).

Functions in Neurodegeneration

Beneficial Functions

DAM may play protective roles in early disease stages:

  • Amyloid clearance: Upregulated phagocytic genes enhance amyloid-beta uptake and degradation

  • Lipid metabolism: Apoe-mediated cholesterol efflux supports membrane remodeling in stressed neurons

  • Trophic support: Secretion of growth factors and anti-inflammatory molecules

Harmful Functions

In later disease stages, DAM become neurotoxic:

  • Chronic inflammation: Production of IL-1β, TNF-α, IL-6, and other pro-inflammatory cytokines

  • Synaptic pruning: Complement-mediated elimination of synapses and neurons

  • Nitrosative stress: Generation of reactive nitrogen species that damage macromolecules

Role in Alzheimer’s Disease

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). Therapeutic strategies targeting TREM2 signaling aim to enhance beneficial DAM functions while suppressing harmful inflammation.

Role in Parkinson’s Disease

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). DAM in PD likely contribute to dopaminergic neuron loss through chronic neuroinflammation and may participate in alpha-synuclein propagation.

Therapeutic Implications

Modulating DAM represents a promising therapeutic approach:

  • TREM2 agonists: Enhance beneficial phagocytosis while dampening inflammation

  • CSF1R inhibitors: Prevent DAM accumulation in advanced disease

  • Anti-inflammatory strategies: Suppress harmful cytokine production

  • Lipid metabolism modulators: Shift DAM toward neuroprotective phenotypes

See Also

  • [Cell-Types/Disease-Associated-Microglia — This page

](/diseases/cell-types/disease-associated-microglia-—-this-page)## Background

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.

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