Posted 3 March 2005

General Information

Transgene: Human tau minigene that overexpresses three human brain tau isoforms with 3RT was created in pKS vector by embedding a modified genomic version of tau exons 1 to 4 (containing introns that flank exons 2 and 3) in a cDNA for the shortest tau isoform (exons -1 to 13 without exons 4A, 6, 8, and 10). The tubulin Tα1 promoter was cloned into pcDNA3 vector, and the XmnI site on pcDNA3 was modified to an AscI site. Transgenic construct (Tα1-3RT) was made by ligating a SalI/PvuII fragment of the minigene construct into a KpnI/NotI-fragment of the Tα-1 promoter vector. The Tα1-3RT was cut, purified, microinjected into fertilized B6SJL/F1 mouse eggs, and reimplanted into pseudopregnant females. Line 14 with the highest transgene copy number and highest tau protein expression was propagated and used.

Promoter: Mouse tubulin Tα1 promoter

Mutation: Tau 3 human RT

Mouse strain: B6SJL, maintained as heterozygous

Phenotype

Neuropathological Analysis:

Generated a tau Tg mouse model of FTD that developed glial tau pathologies. Progressive accumulations of tau in astrocytes and oligodendrocytes were closely associated with degeneration of these cells as well as with disruption of myelin sheaths. Aged Tg mice showed numerous glial tau inclusions that were morphologically, histochemically, and immunohistochemically similar to the glial tau pathologies in FTDs, such as PSP, PiD, PSG, CBD, and FTDP-17.

Behavioral:

Mice developed progressive motor weakness, including impaired ability to stand on a slanted surface and dystonic movement of the hindlimbs or both hindlimbs and forelimbs when lifted by their tails. By 24 months of age, limb twitch was observed in 72% of Tg mice, compared with 18% of WT mice.

Availability

Virginia M. -Y. Lee
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine
Philadelphia, PA 19104 USA
Phone: 215-662-6427
Fax: 215-349-5909
Email: vmylee@mail.med.upenn.edu

Patents:

References

Primary:

Higuchi M, Ishihara T, Zhang B, Ming Hong M, Andreadis A, Trojanowski J Q, and Lee V M-Y. Transgenic Mouse Model of Tauopathies with Glial Pathology and Nervous System Degeneration. Neuron 35:433-446, 2002. Abstract.

Associated:

Macknin J B, Higuchi M, Lee V M-Y, Trojanowski J Q and Doty R L. Olfactory dysfunction occurs in transgenic mice overexpressing human t protein. Brain Res. 1000:174-178, 2004. Abstract.