Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Genetic Background: B6C3F1 embryos, backcrossed to C57BL/6
Availability: Available through Hiroshi Mori and Takami Tomiyama

Summary

Tau264 transgenic mice express low levels of wild-type human tau. This model does not develop neuropathology or behavioral deficits, but can be used to study the interaction of human tau with other proteins, such as Aβ and α-synuclein, by crossbreeding with other mouse models.

Transgene expression in these mice is driven by a minigene that includes intronic regions flanking exon 10, such that endogenous splicing machinery executes physiological splicing of exon 10. Splicing generates tau transcripts that either contain exon 10 (exon10⁺) or exclude it (exon10^-). Respectively, these transcripts generate isoforms containing four microtubule binding repeat domains (4R tau) or three microtubule binding repeat domains (3R tau). Transgene expression is developmentally regulated such that only 3R human tau is expressed at a young age, whereas 3R tau and 4R tau are expressed at similar levels in adults. Overall transgene expression is low, about 10 percent of endogenous mouse tau expression in heterozygous animals.

The transgene expresses the longest brain isoforms of 3R and 4R tau, respectively, i.e., tau410 (2N3R) and tau441 (2N4R). The mice also express endogenous murine tau: 3R and 4R as juveniles and 4R as adults. Therefore, any tau inclusions induced in this model may contain both human and mouse tau.

This model was first reported as the control strain for Tau609, a transgenic expressing human tau with the 10+16 intronic mutation (Umeda et al., 2013). In addition to serving as a control, it is considered a useful model for crossing with other disease models to determine how the presence of wild-type human tau affects phenotype development. For example, the presence of human tau accelerated disease phenotypes in the APP transgenic line, APP E693Δ, resulting in greater neuropathology and cognitive impairment. In addition, the double transgenic progeny developed neurofibrillary tangles, a phenotype not observed in either of the parental strains (Umeda et al., 2014).

Modification Details

The tau construct (iEi10) contains the first 18 nucleotides and the last 3.0 kb of MAPT intron 9 and the first 3.0 kb and the last 38 nucleotides of intron 10 at the corresponding sides of exon 10 in the tau isoform 441. The minigene is driven by the mouse CAMKIIα promoter.

Availability

For information regarding the availability of this model, contact Hiroshi Mori or Takami Tomiyama.

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References

Research Models Citations

1. Tau609 (Tau 10 + 16)

Paper Citations

1. Umeda T, Yamashita T, Kimura T, Ohnishi K, Takuma H, Ozeki T, Takashima A, Tomiyama T, Mori H. Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice. Am J Pathol. 2013 Jul;183(1):211-25. PubMed.
2. Umeda T, Maekawa S, Kimura T, Takashima A, Tomiyama T, Mori H. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol. 2014 May;127(5):685-98. Epub 2014 Feb 15 PubMed.

Other Citations

1. APP E693Δ

Further Reading