Human microglial state dynamics in Alzheimer’s disease progression
Na Sun, Matheus B. Victor, Yongjin Park, Xushen Xiong, Aine Ni Scannail, Noelle Leary, Shaniah Prosper, Soujanya Viswanathan, Xochitl Luna, Carles A. Boix, Benjamin T. James, Yosuke Tanigawa, Kyriaki Galani, Hansruedi Mathys, Xueqiao Jiang, Ayesha P. Ng, David A. Bennett, Li‐Huei Tsai, Manolis Kellis
Abstract
Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.