Intron-3 retention/splicing controls neuronal expression of apolipoprotein E in the CNS

J Neurosci. 2008 Feb 6;28(6):1452-9. doi: 10.1523/JNEUROSCI.3253-07.2008.


Neuronal expression of apolipoprotein (apo) E4 may contribute to the pathogenesis of Alzheimer's disease (AD). In studying how apoE expression is regulated in neurons, we identified a splicing variant of apoE mRNA with intron-3 retention (apoE-I3). ApoE-I3 mRNA was detected in neuronal cell lines and primary neurons, but not in astrocytic cell lines or primary astrocytes, from humans and mice by reverse transcription (RT)-PCR. In both wild-type and human apoE knock-in mice, apoE-I3 was found predominantly in cortical and hippocampal neurons by in situ hybridization. Cell fractionation and quantitative RT-PCR revealed that over 98% of the apoE-I3 mRNA was retained in the nucleus without protein translation. In transfected primary neurons, apoE expression increased dramatically when intron-3 was deleted from a genomic DNA construct and decreased markedly when intron-3 was inserted into a cDNA construct, suggesting that intron-3 retention/splicing controls apoE expression in neurons. In response to excitotoxic challenge, the apoE-I3 mRNA was markedly increased in morphologically normal hippocampal neurons but reduced in degenerating hippocampal neurons in mice; apoE mRNA showed the opposite pattern. This apparent precursor-product relationship between apoE-I3 and apoE mRNA was supported by a transcriptional inhibition study. Thus, neuronal expression of apoE is controlled by transcription of apoE-I3 under normal conditions and by processing of apoE-I3 into mature apoE mRNA in response to injury.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoproteins E / biosynthesis*
  • Apolipoproteins E / genetics*
  • Apolipoproteins E / metabolism
  • Cell Line
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Gene Expression Regulation / physiology*
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Humans
  • In Situ Hybridization
  • Introns / physiology*
  • Mice
  • Mice, Mutant Strains
  • Neurons / metabolism*
  • RNA Processing, Post-Transcriptional / physiology
  • RNA Splicing / physiology*


  • Apolipoproteins E