Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution
Hansruedi Mathys,
Chinnakkaruppan Adaikkan,
Fan Gao,
Jennie Z. Young,
Elodie Manet,
Martin Hemberg,
Philip L. De Jager,
Richard M. Ransohoff,
Aviv Regev,
Li-Huei Tsai
Affiliations
Hansruedi Mathys
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Chinnakkaruppan Adaikkan
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Fan Gao
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Jennie Z. Young
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Elodie Manet
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Martin Hemberg
Department of Cellular Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK
Philip L. De Jager
Center for Translational and Systems Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Richard M. Ransohoff
Biogen, 225 Binney Street, Cambridge, MA 02142, USA
Aviv Regev
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Li-Huei Tsai
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Summary: Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer’s disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stage-specific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs. : Mathys et al. use single-cell RNA sequencing to determine the phenotypic heterogeneity of microglia during the progression of neurodegeneration. They identify multiple disease stage-specific cell states, including two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Keywords: microglia, Alzheimer’s disease, neurodegeneration, single-cell RNA sequencing
