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Related Experiment Video

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APOE4 confers transcriptomic and functional alterations to primary mouse microglia.

Saima I Machlovi1, Sarah M Neuner2, Brittany M Hemmer1

  • 1Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ronald M. Loeb Center for Alzheimer's Disease, Nash Family Department of Neuroscience, Friedman Brain Institute, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Neurobiology of Disease
|January 15, 2022
PubMed
Summary

The Alzheimer's disease (AD) risk variant Apolipoprotein E ε4 (APOE4) alters microglial function, increasing cellular stress and phagocytosis compared to APOE3. These changes may explain APOE4's role in AD pathogenesis.

Keywords:
APOE genotypeAlzheimer's diseaseInterferon signalingLipid accumulationLipid dropletsMicrogliaMyelinPhagocytosisTranslation inhibitioneIF2 signaling

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Alzheimer's disease (AD) risk is influenced by genetic variants, particularly Apolipoprotein E (APOE) genotype.
  • Microglia, the brain's immune cells, are implicated in AD etiology, with risk alleles enriched in myeloid cell enhancers.
  • The specific impact of APOE genotype on microglial function remains largely uncharacterized.

Purpose of the Study:

  • To investigate the functional consequences of APOE ε4 (E4) genotype on primary microglia compared to APOE ε3 (E3) genotype.
  • To elucidate the molecular and cellular mechanisms underlying APOE4's increased risk for Alzheimer's disease.

Main Methods:

  • Primary microglia were cultured from humanized APOE ε3 and APOE ε4 mouse models.
  • Microglial morphology, cellular stress markers (e.g., integrated stress response), lipid accumulation, and phagocytic activity were assessed.
  • Transcriptomic profiling was performed on microglia under baseline and myelin-challenged conditions.

Main Results:

  • APOE4 microglia exhibited altered morphology, increased endolysosomal mass, elevated cytokine production, and greater lipid accumulation compared to APOE3 microglia.
  • APOE4 microglia showed signs of increased cellular stress, including decreased translation and elevated eIF2ɑ phosphorylation.
  • APOE4 microglia demonstrated enhanced phagocytic uptake of myelin and other substrates.
  • Differential gene expression in interferon signaling, extracellular matrix, and translation pathways was observed in APOE4 microglia.

Conclusions:

  • The APOE4 genotype confers significant functional alterations to microglia, even in the absence of external challenges.
  • These APOE4-associated microglial dysfunctions, including heightened cellular stress and phagocytosis, provide mechanistic insights into how APOE4 increases Alzheimer's disease risk.