Updated 8 January 2004

General Information

Transgene: A 5.5-kb genomic fragment of the human ApoE4 gene, including the four exons and three introns. Microinjected into FVB/N embryos.

Mutation: hApoE4

Targeted region (if applicable):     brain, neurons

Promoter: Mouse Thy-1, human platelet-derived growth factor (PDGF), human glial fibrillary acidic protein (GFAP)or mouse phosphoglycerate kinase (PGK) promoters.

Intron: : * intron 1a, 1b and 2 of the mouse thy1 gene are retained in the mini-gene
            * introns 1 to 4 in the human ApoE gene retained intact

Mouse strain: Origin: C57BL/6

Phenotype

Null mutant phenotype:     N/A

Lethality/viability/fecundity:     normal for all parameters.

Homozygous/heterozygous viability: Homozygous thy1-ApoE4 mice develop motoric problems (6-9 months) progressively worsening and causing prematured death (12-18 months).

Relative Protein expression level to endogenous
Beta Amyloid:    NA
Presenilin:     NA
Tau: NA, but endogenous mouse protein tau is becoming hyperphosphorylated in older mice, which is highly correlated with the motoric problems (see below)

Neuropathological analysis

Thy-1-ApoE4 and PDGE-ApoE4 tg mice expressed hApoE4 in neurons. This expression resulted in hyperphosphorylation of protein tau (increased with age) and morphological neuronal changes in the brain, astrogliosis and ubiquitin-positive inclusions. This contributed to disruption of axonal transport and axon degeneration. GFAP-ApoE4 tg mice express hApoE4 in astrocytes and no symptoms were observed. Transgenic human ApoE4 was also expressed in spinal cord for all tg mice with levels of Thy-1-ApoE4 at 3.5-12 x PDGF-ApoE4 and GFAP-ApoE4 at 6.7x PDGF-ApoE4

Behavioral

All tg mice from all constructs appeared normal the first 2-3 months. Progressed to manifest motor problems accompanied by muscle wasting, loss of total body weight and premature death. Observed earliest in Thy1-ApoE4 at 3-12 months, by 6 months 25%-66% had died. Less severe phenotype characteristics seen in PDGF-ApoE4 and PGK-ApoE4 at 12months or older with mortality similar to non-tg.

Availability

Licensing/academic distribution contact information:

Paul Van Dun
Director - KULeuvenR&D
Groot Begijnhof 59
B-3000 Leuven Belgium
tel +32 16 326508
fax +32 16 326515
Email: Paul.Vandun@lrd.kuleuven.ac.be
Web site: http://www.kuleuven.ac.be/lrd

Patents: None

References

Primary:

Tesseur I., Van Dorpe J., Bruynseels K., Sciot R., Van Lommel A., Van Leuven F. Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human Apolipoprotein E4 in neurons of brain and spinal cord. Am. J. Pathol. (2000 Nov) 157(5):1495-510. Abstract.

Associated:

Tesseur I., Van Dorpe J., Spittaels K., Van den Haute C., Moechars D., Van Leuven F. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein tau in the brains of transgenic mice. Am J Pathol. (2000) 56 : 951-964. Abstract.

Umans L., Serneels L., Lorent K., Dewachter I., Tesseur I., Moechars D., Van Leuven F. Lipoprotein receptor-related protein in brain and in cultured neurons of mice deficient in receptor-associated protein and transgenic for apoliprotein E4 or amyloid precursor protein. Neuroscience (1999) 94 : 315-321 Abstract.