Human microglial state dynamics in Alzheimer's disease progression

Na Sun; Matheus B Victor; Yongjin P 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

doi:10.1016/j.cell.2023.08.037

Human microglial state dynamics in Alzheimer's disease progression

Cell. 2023 Sep 28;186(20):4386-4403.e29. doi: 10.1016/j.cell.2023.08.037.

Authors

Na Sun¹, Matheus B Victor², Yongjin P Park³, Xushen Xiong¹, Aine Ni Scannail², Noelle Leary², Shaniah Prosper², Soujanya Viswanathan², Xochitl Luna², Carles A Boix¹, Benjamin T James¹, Yosuke Tanigawa¹, Kyriaki Galani¹, Hansruedi Mathys⁴, Xueqiao Jiang², Ayesha P Ng², David A Bennett⁵, Li-Huei Tsai⁶, Manolis Kellis⁷

Affiliations

¹ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
³ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Pathology and Laboratory Medicine, Department of Statistics, University of British Columbia, Vancouver, BC, Canada; Department of Molecular Oncology, BC Cancer, Vancouver, BC, Canada.
⁴ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁵ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: lhtsai@mit.edu.
⁷ MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: manoli@mit.edu.

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.

Keywords: Alzheimer's; cell states; disease-stage response; iPSCs; inflammation; microglia; single-cell; transcription factors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / pathology
Epigenome
Gene Expression Regulation
Humans
Inflammation / pathology
Microglia* / metabolism
Transcription Factors / metabolism
Transcriptome

Substances

Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding