Biomedical
Microglia Heterogeneity in Alzheimer’s Disease: Insights From Single-Cell Technologies
Abstract
Microglia are resident immune cells in the central nervous system and play critical roles in brain immunity, development, and homeostasis. The pathology of Alzheimer’s disease (AD) triggers activation of microglia. Microglia express many AD risk genes, suggesting that their response to AD pathology can affect disease progression. Microglia have long been considered a homogenous cell population. The diversity of microglia has gained great interest in recent years due to the emergence of novel single-cell technologies, such as single-cell/nucleus RNA sequencing and single-cell mass cytometry by time-of-flight. This review summarizes the current knowledge about the diversity/heterogeneity of microglia and distinct microglia states in the brain of both AD mouse models and patients, as revealed by single-cell technologies. It also discusses the future developments for application of single-cell technologies and the integration of these technologies with functional studies to further dissect microglia biology in AD. Defining the functional correlates of distinct microglia states will shed new light on the pathological roles of microglia and might uncover new relevant therapeutic targets for AD.
What are microglia and why are they important in Alzheimer's disease?
Microglia are:- Resident immune cells in the central nervous system
- Critical for brain immunity, development, and homeostasis
- Activated in response to Alzheimer's disease pathology
- Express many Alzheimer's disease risk genes, suggesting they can affect disease progression
How have single-cell technologies advanced our understanding of microglia in Alzheimer's disease?
Single-cell technologies have:- Revealed the diversity and heterogeneity of microglia
- Identified distinct microglia states in Alzheimer's disease mouse models and patients
- Enabled high-throughput profiling of individual cells
- Allowed transcriptomic analysis of single cells from postmortem human tissues
- Facilitated analysis of multiple surface markers at the single-cell level
What are some key microglia states identified in Alzheimer's disease?
Key microglia states include:- Disease-associated microglia (DAM)
- Interferon-responsive microglia
- Activated response microglia (ARM)
- White matter-associated microglia (WAM)
What are the characteristics of disease-associated microglia (DAM)?
DAM are characterized by:- Reduced expression of homeostatic genes (e.g., P2ry12, Cx3cr1, Tmem119)
- Upregulation of genes involved in lysosomal/phagocytic pathways
- Expression of Alzheimer's disease risk genes (e.g., Apoe, Trem2)
- Localization near amyloid-β plaques
- A two-stage activation process: TREM2-independent followed by TREM2-dependent
