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Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau

Silvia S Kang1, Mark T W Ebbert2, Kelsey E Baker2

  • 1Department of Neuroscience, Mayo Clinic, Jacksonville, FL kang.silvia@mayo.edu.

The Journal of Experimental Medicine
|August 8, 2018
PubMed

Insights

This study reveals a common APOE-driven network in microglia altered by Alzheimer's disease (AD) and aging. Aged females show exacerbated changes, suggesting a mechanism for increased AD susceptibility.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Alzheimer's disease (AD) is linked to aging, amyloidosis, tauopathy, and microglial activation.
  • Microglia are key innate immune cells in the brain, and their transcriptomic changes are crucial in AD pathogenesis.
  • Existing methods for studying microglia can introduce biases.

Purpose of the Study:

  • To identify common microglial transcriptomic alterations in models of AD and aging.
  • To uncover networks driving these changes, particularly those involving APOE.
  • To investigate sex-specific differences in microglial responses relevant to AD susceptibility.

Main Methods:

  • Utilized RiboTag translational profiling to analyze microglial gene expression without cell sorting biases.
  • Applied this method to mouse models of amyloidosis, tauopathy, and aging.
  • Integrated data to identify conserved and condition-specific transcriptomic changes.

Main Results:

  • Identified a shared set of microglial transcriptomic alterations across amyloidosis, tauopathy, and aging models.
  • Discovered a central APOE-driven network converging on CCL3 and CCL4.
  • Observed significant exacerbation of APOE network transcripts in aged female mice, indicating higher AD susceptibility.

Conclusions:

  • RiboTag profiling offers an unbiased approach for studying microglial transcriptomics.
  • A common APOE-driven network is implicated in AD and aging.
  • Exacerbated microglial responses in aged females may explain their increased AD risk.

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