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

doi:10.1016/j.celrep.2017.09.039

Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution

Cell Rep. 2017 Oct 10;21(2):366-380. doi: 10.1016/j.celrep.2017.09.039.

Authors

Affiliations

¹ 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.
² Department of Cellular Genetics, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
³ 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.
⁴ Biogen, 225 Binney Street, Cambridge, MA 02142, USA.
⁵ 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.
⁶ 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. Electronic address: [email protected].

Abstract

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.

Keywords: Alzheimer’s disease; microglia; neurodegeneration; single-cell RNA sequencing.

MeSH terms

Alzheimer Disease / metabolism*
Animals
Brain / cytology
Brain / metabolism
Cells, Cultured
Gene Expression Profiling
Interferon Type I / genetics
Interferon-gamma / genetics
Macrophage Activation*
Macrophages / metabolism
Mice
Microglia / cytology
Microglia / metabolism*
Phenotype
Single-Cell Analysis
Transcriptome*

Substances

Interferon Type I
Interferon-gamma

Abstract

MeSH terms

Substances

Grants and funding