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

TLDR

Microglia are CNS‑resident immune cells whose full spectrum of activation states remains poorly defined. The study aims to map CNS myeloid activation dimensions in human disease to uncover therapeutic targets. The authors derived co‑regulated gene modules from diverse mouse myeloid transcriptomes, applied them to human AD RNA‑seq and single‑cell data, and released an interactive database for exploration. They uncovered microglial subsets in AD distinct from disease‑associated microglia, expressing interferon‑related or proliferation modules, and identified elevated neurodegeneration modules plus additional modules absent in mouse models.

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.