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Cell Rep. 2018 Jan 16;22(3):832-847. doi: 10.1016/j.celrep.2017.12.066.

Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models.

Author information

1
Department of Bioinformatics and Computational Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: friedman.brad@gene.com.
2
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
3
Department of Bioinformatics and Computational Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
4
Department of Biomarker Discovery OMNI, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
5
Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
6
Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
7
Department of Bioinformatics and Computational Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
8
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: hansen.david@gene.com.

Abstract

Microglia, the CNS-resident immune cells, play important roles in disease, but the spectrum of their possible activation states is not well understood. We derived co-regulated gene modules from transcriptional profiles of CNS myeloid cells of diverse mouse models, including new tauopathy model datasets. Using these modules to interpret single-cell data from an Alzheimer's disease (AD) model, we identified microglial subsets-distinct from previously reported "disease-associated microglia"-expressing interferon-related or proliferation modules. We then analyzed whole-tissue RNA profiles from human neurodegenerative diseases, including a new AD dataset. Correcting for altered cellular composition of AD tissue, we observed elevated expression of the neurodegeneration-related modules, but also modules not implicated using expression profiles from mouse models alone. We provide a searchable, interactive database for exploring gene expression in all these datasets (http://research-pub.gene.com/BrainMyeloidLandscape). Understanding the dimensions of CNS myeloid cell activation in human disease may reveal opportunities for therapeutic intervention.

KEYWORDS:

Alzheimer’s disease; FACS; RNA-seq; gene expression; microglia; microgliosis; myeloid; neurodegeneration; neuroinflammation; tauopathy

PMID:
29346778
DOI:
10.1016/j.celrep.2017.12.066
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