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The Journal of Neuroscience, May 10, 2006, 26(19):4985-4994; doi:10.1523/JNEUROSCI.5476-05.2006

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Neurobiology of Disease
Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus

Qin Xu,^1,2 Aubrey Bernardo,¹ David Walker,¹ Tiffany Kanegawa,¹ Robert W. Mahley,^1,2,4,5 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 ³Neurology, ⁴Pathology, and ⁵Medicine, 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

To study the profile and regulation of apolipoprotein E (apoE) expression in the CNS, we generated mice in which apoE expression can be detected in vivo with unprecedented sensitivity and resolution. cDNA encoding enhanced green fluorescent protein (EGFP) with a stop codon was inserted by gene targeting into the apoE gene locus (EGFP_apoE) immediately after the translation initiation site. Insertion of EGFP into one apoE allele provides a real-time location marker of apoE expression in vivo; the remaining allele is sufficient to maintain normal cellular physiology. In heterozygous EGFP_apoE mice, EGFP was highly expressed in hepatocytes and peritoneal macrophages. EGFP was also expressed in brain astrocytes; however some astrocytes (25%) expressed no EGFP, suggesting that a subset of these cells does not express apoE. EGFP was expressed in <10% of microglia after kainic acid treatment, suggesting that microglia are not a major source of brain apoE. Although hippocampal neurons did not express EGFP under normal conditions, kainic acid treatment induced intense expression of EGFP in injured neurons, demonstrating apoE expression in neurons in response to excitotoxic injury. The neuronal expression was confirmed by in situ hybridization of mouse apoE mRNA and by anti-apoE immunostaining. Smooth muscle cells of large blood vessels and cells surrounding small vessels in the CNS also strongly expressed EGFP, as did cells in the choroid plexus. EGFP_apoE reporter mice will be useful for studying the regulation of apoE expression in the CNS and might provide insights into the diverse mechanisms of apoE4-related neurodegeneration.

Key words: apolipoprotein E; Alzheimer's disease; green fluorescent protein; excitotoxin; knock-in mice; gene regulation

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Received Dec. 21, 2005; revised March 7, 2006; accepted March 30, 2006.

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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