Journal of Alzheimer's Disease
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Home > Apolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro.

TitleApolipoprotein E Isoforms Differentially Regulate Alzheimer's Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro.
Publication TypeJournal Article
Year of Publication2017
AuthorsDorey, E, Bamji-Mirza, M, Najem, D, Li, Y, Liu, H, Callaghan, D, Walker, D, Lue, L-F, Stanimirovic, D, Zhang, W
JournalJ Alzheimers Dis
Volume57
Issue4
Pagination1265-1279
Date Published2017
ISSN1875-8908
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.

DOI10.3233/JAD-160133
Alternate JournalJ. Alzheimers Dis.
PubMed ID28372324
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Source URL: https://www.j-alz.com/content/apolipoprotein-e-isoforms-differentially-regulate-alzheimers-disease-and-amyloid-%CE%B2-induced