Microglial Activation States in Alzheimer’s Disease

How single-cell transcriptomics has revealed the diverse activation states of microglia in Alzheimer’s disease, from homeostatic to disease-associated phenotypes.

Microglia: The Brain’s Immune Sentinels

Microglia are the resident macrophages of the central nervous system, constantly surveying the brain parenchyma for damage and pathogens. In Alzheimer’s disease (AD), microglia adopt a range of activation states that can be both neuroprotective and neurotoxic.

Disease-Associated Microglia (DAM)

Single-cell RNA-seq studies in AD mouse models and human post-mortem tissue have identified a conserved transcriptional program termed disease-associated microglia (DAM). Key features include:

• Downregulation of homeostatic genes (P2ry12, Cx3cr1, Tmem119)
• Upregulation of lipid metabolism and phagocytosis genes (Apoe, Lpl, Trem2)
• A TREM2-dependent transition from stage 1 to stage 2 DAM

Beyond the DAM Binary

Recent high-resolution atlases have expanded the picture beyond a simple homeostatic-vs-DAM dichotomy, revealing:

• Interferon-responsive microglia enriched near amyloid plaques
• Proliferating microglia associated with disease progression
• Lipid-droplet-accumulating microglia (LDAM) linked to aging

Implications for Therapeutics

Understanding microglial heterogeneity is critical for designing targeted therapies. TREM2 agonists, for example, aim to enhance protective DAM responses while minimizing pro-inflammatory signaling.

Further Reading

• Keren-Shaul et al. (2017). Cell. DOI: 10.1016/j.cell.2017.05.018
• Mathys et al. (2019). Nature. DOI: 10.1038/s41586-019-1195-2