Updated 27 January 2005

General Information

Transgene:     Human longest brain tau isoform, wildtype 4 repeat tau isoform with two N-terminal inserts generated using a recombinant DNA construct.

Mutation:     None

Promoter:   Neuron-specific elements of the mouse Thy.1.2 promoter. The thymus specific regulatory elements in intron 3 are thereby deleted, making the resulting promoter "post-natal" and "neuron specific"

Mouse strain:   B6D2F1 x B6D2F1, founder animals were intercrossed with C57BL/6 mice to establish lines.

Phenotype

Neuropathological Analysis:

In heterozygous mice of strain 4R/2N (htau40-1), the level of human tau protein was about four fold higher than the endogenous mouse tau. 

Axonal degeneration in brain and spinal cord. Axonal dilation with accumulation of neurofilaments, mitochondria, and vesicles.

Although no neuron loss was established, astrogliosis and ubiquitination of accumulated proteins in the dilated part of the axon observed.

No intraneuronal neurofibrillary tangles observed.

Behavioral:

Homozygous transgenic mice flexed their hind limbs when lifted by the tail. Their swimming speed was significantly lower than that of wild-type. This motor disturbance prevented the mice from being tested in the Morris water maze. 

Transgene-dose dependent dysfunction in sensorimotor capacities.

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:

Spittaels K, Van den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, Laenen I, Geerts H, Mercken M, Sciot R, Van Lommel A, Loos R, Van Leuven F. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 1999 Dec;155(6):2153-65. Abstract.

Associated:

Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F.Changed conformation of mutant tau-P301L underlies the moribund tauopathy, absent in progressive, non-lethal axonopathy of tau-4R/2N transgenic mice. J Biol Chem (2005) 280: 3963-3973. Abstract.

Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, Van Lint J, Vandenheede J, Moechars D, Loos R, Van Leuven F. Glycogen synthase kinase-3β phosphorylates protein tau and rescues the anonopathy in the CNS of human four-repeat tau transgenic mice. J Biol Chem 2000, 275:41640-41349. Abstract.

Nuydens R, Van den Kieboom G, Nolten C, Verhulst C, Van Osta P, Spittaels K, Van den Haute C, De Feyter E, Geerts H, Van Leuven F. Coexpression of GSK-3 [beta] corrects phenotypic aberrations of dorsal root ganglion cells, cultured from adult transgenic mice overexpressing human protein tau. Neurobiol Dis 2002, 9:38-48. Abstract.