title: Apolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro.
abstract: 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.
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Evan
authors.initials: E
authors.lastname: Dorey
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bamji-Mirza
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Dema
authors.initials: D
authors.lastname: Najem
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Debbie
authors.initials: D
authors.lastname: Callaghan
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Walker
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Lih-Fen
authors.initials: LF
authors.lastname: Lue
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Danica
authors.initials: D
authors.lastname: Stanimirovic
authors.affiliation: Faculty of Medicine, University of Ottawa, Ottawa, Canada.|Human Health Therapeutics, National Research Council Canada, Ottawa, Canada.
authors.forename: Wandong
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology*; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D000066829:Neuroprotection / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism; D020033:Protein Isoforms; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D020033:Protein Isoforms; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42); D014807:Vitamin D; C031271:1-alpha, 25-difluorovitamin D3
keywords: Alzheimer’s disease; ApoE isoform proteins; amyloid-β peptides; neuroinflammation; vitamin D receptorsignaling