Disease Associated Microglia: A Universal Immune Sensor of Neurodegeneration

Microglia are the resident immune cells of the central nervous system (CNS). Over the last decades, microglia has been shown to play an important role in development, degeneration and homeostasis of the CNS. Alzheimer’s disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we characterized the immune cells in AD and discovered a novel microglia type associated with neurodegenerative diseases (DAM) and identified markers, spatial localization, and pathways (such as Trem2) associated with these cells. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. We further performed a large cross-species analysis of microglia throughout evolution, characterizing the microglia transcriptional program across ten species spanning more than 450 million years of evolution. We found that microglia express a conserved core gene program of orthologous genes from rodents to human, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, while human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents as compared to primate microglia; including complement, phagocytic and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. This study provides an essential resource of conserved and divergent microglia pathways across evolution with important implications for future development of microglia-based therapies in humans.