Apolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro

J Alzheimers Dis. 2017;57(4):1265-1279. doi: 10.3233/JAD-160133.


Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3. Cells and media were harvested for cytokine ELISA, RNA isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Aβ42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Aβ42-induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Aβ42-induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Aβ42-treated astrocytes. Application of 1α,25-dihydroxyvitamin D3 completely inhibited Aβ-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Aβ-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration.

Keywords: Alzheimer’s disease; ApoE isoform proteins; amyloid-β peptides; neuroinflammation; vitamin D receptorsignaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / immunology*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Apolipoproteins E / administration & dosage
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Astrocytes / drug effects
  • Astrocytes / immunology*
  • Brain / drug effects
  • Brain / immunology*
  • Brain / pathology
  • Cells, Cultured
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Neuroimmunomodulation / drug effects
  • Neuroimmunomodulation / physiology
  • Neuroprotection / drug effects
  • Neuroprotection / physiology
  • Neuroprotective Agents / pharmacology
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / metabolism
  • Protein Isoforms
  • Rats, Sprague-Dawley
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / metabolism
  • Vitamin D / analogs & derivatives
  • Vitamin D / pharmacology


  • Amyloid beta-Peptides
  • Apolipoproteins E
  • Neuroprotective Agents
  • Peptide Fragments
  • Protein Isoforms
  • Recombinant Proteins
  • amyloid beta-protein (1-42)
  • Vitamin D
  • 1-alpha, 25-difluorovitamin D3