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

Brad A Friedman,Karpagam Srinivasan,Gai Ayalon,William J Meilandt,Han Lin,Melanie A Huntley,Yi Cao,Seung-Hye Lee,Patrick C.G Haddick,Hai Ngu,Zora Modrusan,Jessica L Larson,Joshua S Kaminker,Marcel P Van Der Brug,David V Hansen

doi:10.1016/j.celrep.2017.12.066

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 theneurodegeneration-related modules, but also modules not implicated using expression profiles from mouse models alone. We provide a searchable, interactive database for exploring gene expression inall 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.

Highlights

Microglia and other mononuclear phagocytes of the CNS are the primary cellular responders to CNS injury or infection (Rivest, 2009). These cells originate during embryonic development when erythromyeloid progenitor cells from the yolk sac colonize the CNS and give rise to microglial cells in parenchymal tissue and to perivascular, meningeal, and choroid plexus macrophages at the interfaces between CNS and peripheral tissues (Alliot et al, 1999; Ginhoux et al, 2010)
The scope of information gained from histological studies can be limited or even misconstrued when microglial cells are classified into purported states of polarization—such as the formerly used ‘‘M1’’ and ‘‘M2’’ macrophage states—using only a handful of markers (Heppner et al, 2015; Ransohoff, 2016)
Surprised that relatively few genes were differentially expressed in microglia from the P301L tau model (Data S7, panel 4E), we directly investigated the neurodegenerationrelated gene set in the P301S and P301L models

Summary

Graphical Abstract

In this meta-analysis of CNS myeloid cell expression profiles, Friedman et al identify gene modules associated with diverse microglial activation states. These modules identify distinct subsets of microglia in an Alzheimer’s model and reveal aspects of the human disease not apparent in mouse models. Highlights d Meta-analysis of purified mouse CNS myeloid cell profiles from 69 different conditions d 7 co-regulated gene sets include one enriched in neurodegenerative disease models d Distinct classes of activated microglia identified in Alzheimer’s mouse model d Resources for further exploration: comprehensive Excel tables and interactive website. 2018, Cell Reports 22, 832–847 January 16, 2018 a 2017 The Author(s).

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EXPERIMENTAL PROCEDURES