The Role of Disease-Associated Microglia in Neurodegenerative Disease: A Review

Abstract

Microglia are tissue-resident macrophages of the central nervous system and peripheral nervous system and mediate homeostasis, surveillance and clearance of foreign particles, and neuroinflammation. Advancements in single-cell RNA sequencing analyses have enabled the identification of a novel subset of microglia, termed disease-associated microglia (DAM), which localize to sites of neurodegeneration and exhibit a unique transcriptional and functional signature. This review examines characteristics of DAM, activation patterns, and specific implications for DAM in Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Sources were identified from the NCBI PubMed database through a database search as well as manual identification. Keywords such as “disease-associated microglia” and “neurodegenerative” were incorporated into the search method and results were compiled into a literature review. Results show a consistent shift in gene expression in DAM, including downregulation of homeostatic genes, such as P2ry12, Cx3cr1, and Tmem119, and upregulation of phagocytic and metabolic genes, such as Apoe, Lpl, Trem2, and Itgax. Additionally, DAM recognize neurodegeneration-associated molecular patterns (NAMPs) across multiple pathologies and may become activated in a two-step sequential process, in which TREM2 is required for full transcriptional activation. Our results suggest that DAM exhibit a unique transcriptional and functional signature relative to other microglial subsets and that future research is necessary to understand whether DAM contribute to or ameliorate neurodegeneration, offering potential insights for druggable targets.