Posted 22 May 2005

General Information

Transgene: The apoE4 minigene consists of part of the untranslated exon 1 (from the AvrII site), the first intron, third intron and the first 6 bp of exon 2 from the human APOE gene, a fragment of human apoE cDNA contributing the entire apoE coding region, and a genomic segment representing exon 4 noncoding sequence and 112 bp of 3' untranslated region including the polyadenylation signal. There was a base change in exon 4 encoding arginine (R) in apoE4 at aa position 112.The NSE-apoE4 transgene was injected into one-cell embryos (ICR strain). NSE-apoE4 tg line was crossed with Apoe-/- mice (Taconic #APOE-M) to eliminate wild-type Apoe alleles. Then crossed with Apoe-/- mice (TJL #2052) to generate NSE-apoE4 mice that were at least 75% C57BL/6J.

Promoter: Rat neuron-specific enolase promoter

Mouse strain: Origin: C57BL/6J; Backcrossed with murine apoE-null mice, N>20

Phenotype

Neuropathological analysis

Neuronal apoE expression was widespread in the brains of these mice. Expression of apoE4 did not protected against excitotoxin (Kainic acid)-induced neuronal damage.

Behavioral

NSE-apoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and were seen primarily in females.

Availability

Licensing/academic distribution contact information:

Dr. Robert W. Mahley
Gladstone Institute of Neurological Disease
1650 Owens Street
San Francisco, CA 94158
Phone: 415-734-2000
Fax: 415-355-0820
Email: rmahley@gladstone.ucsf.edu

Patents: Patent Number: 6,046,381; Title: Apolipoprotein E Transgenic Mice and Assay Methods; Inventors: Mucke, L., Raber, J., Buttini, M., Mahley, R.W., Pitas, R.E.; Filing Date: 4/30/1998; Issue Date: 4/4/2000

References

Primary:

Raber J, Wong D, Buttini M, Orth M, Bellosta S, Pitas RE, Mahley RW, Mucke L. Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci U S A 95(18):10914-9, 1998. Abstract.

Associated:

Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss-Coray, T., Mucke, L. & Mahley, R. W. Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. J. Neurosci. 19, 4867-4880, 1999. Abstract

Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J Biol Chem. 279(43):44795-801, 2004. Abstract

Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Dee Fish J, Wyss-Coray T, Buttini M, Mucke L, Mahley RW, Huang Y. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004 Mar 10;24(10):2527-34. Abstract

Buttini M, Akeefe H, Lin C, Mahley RW, Pitas RE, Wyss-Coray T, Mucke L. Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. Neuroscience. 2000;97(2):207-10. Abstract