Molecular Neurobiology

, Volume 48, Issue 3, pp 669–680

Binding and Repressive Activities of Apolipoprotein E3 and E4 Isoforms on the Human ApoD Promoter

  • Louis-Charles LevrosJr.
  • Marilyne Labrie
  • Cyndia Charfi
  • Eric Rassart
Article

Abstract

Apolipoprotein D (ApoD) gene expression is increased in several neurological disorders such as Alzheimer’s disease (AD) and multiple sclerosis. We previously showed that transgenic mice that overexpress human ApoD show a better resistance against paraquat or OC43 coronavirus-induced neurodegeneration. Here, we identified several nuclear factors from the cortex of control and OC43-infected mice which bind a fragment of the proximal ApoD promoter in vitro. Of interest, we detected apolipoprotein E (ApoE). Human ApoE consists of three isoforms (E2, E3, and E4) with the E4 and E2 alleles representing a greater and a lower risk for developping AD, respectively. Our results show that ApoE is located in the nucleus and on the ApoD promoter in human hepatic and glioblastoma cells lines. Furthermore, overexpression of ApoE3 and ApoE4 isoforms but not ApoE2 significantly inhibited the ApoD promoter activity in U87 cells (E3/E3 genotype) cultured under normal or different stress conditions while ApoE knock-down by siRNA had a converse effect. Consistent with these results, we also demonstrated by ChIP assay that E3 and E4 isoforms, but not E2, bind the ApoD promoter. Moreover, using the Allen Brain Atlas in situ hybridization database, we observed an inverse correlation between ApoD and ApoE mRNA expression during development and in several regions of the mouse brain, notably in the cortex, hippocampus, plexus choroid, and cerebellum. This negative correlation was also observed for cortex layers IV–VI based on a new Transcriptomic Atlas of the Mouse Neocortical Layers. These findings reveal a new function for ApoE by regulating ApoD gene expression.

Keywords

Apolipoprotein D Apolipoprotein E OC43 Mass spectrometry ChIP Glioblastoma astrocytic cells 

Supplementary material

12035_2013_8456_MOESM1_ESM.ppt (4.9 mb)
Fig. S1Representative ISH of ApoD and ApoE genes in the mouse cortex during development. These images were obtained from the ABA Website (http://www.brainmap.org) with their corresponding relative gene expression intensities. Comparisons were made throughout development, from E.18.5 to 24 months for ApoD and 33 months for ApoE. (PPT 5051 kb)
12035_2013_8456_MOESM2_ESM.ppt (2.1 mb)
Fig. S2Representative in situ hybridations of ApoD and ApoE genes in the mouse brain. These images were obtained from the ABA Website (http://www.brain-map.org) with their corresponding relative gene expression intensities in different brain areas of 56-day-old mice. a Total brain. b Hippocampus. Field CA1, CA2, CA3, DG, and dentate gyrus. c Cerebral cortex (isocortex). Layers I–VI; CC corpus collasum. d Plexus choroid. e Cerebellar cortex. ML molecular layer, PL Purkinge layer, GL granular layer. (PPT 2174 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Louis-Charles LevrosJr.
    • 1
  • Marilyne Labrie
    • 1
  • Cyndia Charfi
    • 1
  • Eric Rassart
    • 1
    • 2
  1. 1.Laboratoire de biologie moléculaire, Département des Sciences Biologiques, and BioMed, centre de recherches biomédicalesUniversité du Québec à MontréalMontréalCanada
  2. 2.Département des Sciences BiologiquesUniversité du Québec à MontréalMontréalCanada

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