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Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain

Bruce Teter1, Mary Jo LaDu, Patrick M Sullivan

  • 1aGeriatric Research Education and Clinical Center, Veterans Greater Los Angeles Healthcare System bDepartments of Neurology and Medicine, University of California, Los Angeles, California cDepartment of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois dGRECC, Durham Veterans Affairs Medical Center eDepartment of Medicine (Geriatrics), Duke University Medical Center, Durham, North Carolina.

Neuroreport
|June 10, 2016
PubMed

Insights

Apolipoprotein E4 (ApoE4) reduces miR146a levels, a key regulator of innate immunity, in the brain and plasma. This early dysregulation in ApoE4 carriers may explain increased Alzheimer's disease risk.

Area of Science:

  • Neuroimmunology
  • Genetics of Alzheimer's Disease
  • Molecular Biology

Background:

  • Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD).
  • Innate immune toll receptor signaling is disrupted in AD, but ApoE isotype-specific effects are unclear.
  • MicroRNA-146a (miR146a) is a key regulator of toll-like receptor (TLR) signaling, particularly in the brain.

Purpose of the Study:

  • To investigate the impact of Apolipoprotein E (ApoE) isotype on brain and plasma levels of miR146a.
  • To determine if ApoE isotype affects miR146a regulation in the context of familial Alzheimer's disease (AD) pathology.
  • To explore the relationship between miR146a levels and key inflammatory markers in ApoE4 carriers.

Main Methods:

  • Utilized 6-month-old targeted replacement mice expressing either ApoE3 or ApoE4.
  • Included mice with and without mutant familial AD transgenes (5xFAD).
  • Quantified brain and plasma miR146a levels and assessed interleukin receptor-associated kinase-1 (IRAK1) expression.

Main Results:

  • ApoE4 significantly reduced miR146a levels in both brain and plasma compared to ApoE3.
  • Familial AD transgenes increased miR146a, but levels remained lower in ApoE4 mice despite higher amyloid and inflammation.
  • ApoE4 brains exhibited increased IRAK1 expression, inversely correlated with miR146a levels, indicating impaired negative feedback.

Conclusions:

  • ApoE4 causes early, systemic dysregulation of miR146a, a central innate immune regulator.
  • This defect persists in the presence of familial AD pathology and may contribute to ApoE4's role in AD risk.
  • Reduced miR146a-mediated negative feedback in ApoE4 carriers could lead to hypersensitivity to innate immune stimuli, including amyloid-beta.

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