| Disease-Associated Microglia (DAM) | |
|---|---|
| Lineage | Glia > Microglia > Disease-Associated |
| Markers | TREM2, APOE, CLEC7A/Dectin-1, TYROBP/DAP12, CD68, LPL |
| Brain Regions | Brain Parenchyma, Hippocampus, Cortex, Substantia Nigra |
| Disease Vulnerability | Alzheimer's Disease, Parkinson's Disease, ALS, MS |
Disease-Associated Microglia (DAM), also known as neurodegenerative-associated microglia (NAM) or MGnD (microglia in neurodegenerative disease), represent a distinct activation state of brain microglia that emerges in response to neurodegenerative pathology. These cells are characterized by a unique transcriptional signature that distinguishes them from the classical pro-inflammatory (M1) or alternative (M2) activation states described in earlier literature[1]. DAM are found surrounding amyloid plaques in Alzheimer's disease, dopaminergic neuron loss in Parkinson's disease, and in various other neurodegenerative conditions.
Disease-Associated Microglia represent a paradigm shift in our understanding of microglial function in the brain. Rather than simply being destructive immune effectors, DAM appear to play a dual role—both contributing to pathology through neurotoxic inflammation while simultaneously attempting to contain and clear disease-relevant proteins and debris.
The discovery of DAM was enabled by single-cell RNA sequencing studies that revealed a continuum of microglial states in the aging and diseased brain. These studies identified a specific gene expression program that is induced in microglia in response to amyloid pathology, including upregulation of genes involved in phagocytosis, lipid metabolism, and antigen presentation[2].
DAM activation occurs in a staged manner:
Stage 1 DAM (pre-DAM):
Stage 2 DAM (full DAM):
DAM are found in close association with amyloid plaques in AD brain tissue, where they appear to form a protective barrier. Their functions include:
Microglial involvement in tau pathology is more complex:
Genetic variants in TREM2 significantly modify AD risk:
This genetic evidence strongly supports a protective role for TREM2-dependent DAM activation in early AD pathogenesis[3].
In PD, DAM are involved in the response to alpha-synuclein pathology:
Microglial activation in the substantia nigra correlates with dopaminergic neuron loss:
TREM2 Agonists
Anti-inflammatory Approaches
Phagocytosis Enhancement
Metabolic Modulation
Several approaches targeting microglial pathways are in clinical trials:
The study of Disease Associated Microglia (Dam) 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.
Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with Alzheimer's disease. Cell. 2017;170(7):1270-1283.e19. ↩︎
Deczkowska A, Keren-Shaul H, Weiner A, et al. Disease-associated microglia: A universal immune sensor of neurodegeneration. Cell. 2018;173(5):1073-1081. ↩︎
Ulrich JD, Holtzman DM. TREM2 function in Alzheimer's disease and neurodegeneration. ACS Chem Neurosci. 2016;7(4):420-427. ↩︎