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The Journal of Neuroscience, February 6, 2008, 28(6):1452-1459; doi:10.1523/JNEUROSCI.3253-07.2008

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Neurobiology of Disease
Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS

Qin Xu,^1,2 David Walker,¹ Aubrey Bernardo,¹ Jens Brodbeck,^1,2 Maureen E. Balestra,¹ and Yadong Huang^1,2,3,4

¹Gladstone Institute of Neurological Disease and ²Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, and Departments of ³Pathology and ⁴Neurology, University of California, San Francisco, California 94143

Correspondence should be addressed to Dr. Yadong Huang, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: yhuang{at}gladstone.ucsf.edu

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.

Key words: apolipoprotein E; Alzheimer's disease; excitotoxicity; gene regulation; intron retention; knock-in mice

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Received April 17, 2007; revised Nov. 7, 2007; accepted Dec. 15, 2007.

Correspondence should be addressed to Dr. Yadong Huang, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: yhuang{at}gladstone.ucsf.edu

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