Posted 14 February 2012

General Information

Transgene: tetO-MAPT*P301L The transgene consists of the human microtubule-associated protein tau (MAPT). Specifically it contains 4-repeat tau lacking the amino-terminal sequences (4R0N). The tau transgene contains exons 1, 4-5, 7, 9-13, intron 13, and exon 14 and is driven by tetracycline-operon-responsive elevement (TRE).

The control of this transgene (human 4-repeat tau containing the P301L mutation) can be temporally regulated with the tetracycline analog doxycycline (dox). For example, these mice have been breed with mice containing an activator transgene consisting of a tet-off open reading frame downstream of Ca2+-calmodulin kinase II promoter elements, generating bigenic progeny which express regulatable transgenic tau largely restricted to the forebrain (SantaCruz et al., 1995).

Mutation: P301L mutation in human 4-repeat tau

Promoter: Tetracycline operator (tetO) upstream of a cytomegalovirus minimal promoter

Mouse Strain: FVB-Tg(tetO-MAPT*P301L)#Kha/J

Phenotype

Viability: Homozygous mice are not viable. These mice were found to express about 13 units of P301L tau (one unit is equivalent to the level of endogenous murine tau) (SantaCruz et al., 1995).

Neuropathological Analysis:

Note: These phenotypes are associated with a compound genotype created using this strain: Tg(Camk2a-tTA)1Mmay/? Tg(tetO-MAPT*P301L)#Kha/? (see Double-Cross entry). Mice developed pretangles (detected by immunohistochemistry with phospho-tau antibodies) as early as 2.5 months of age. Argyrophilic tanglelike inclusions appeared in the cortex by 4 months and in the hippocampus by 5.5 months, at which time a significant loss in brain weight was also measured. Total numbers of CA1 hippocampal neurons were significantly decreased (~60%) by 5.5 months, and only ~23% of CA1 pyramidal neurons remained at 8.5 months. Gross atrophy of the forebrain was evident by 10 months. Brief suppression of transgenic tau with doxycycline (6 to 8 weeks) had no significant effect on loss of brain weight, but longer suppression (5.5 to ~10 months) significantly protected against the loss of brain weight. The number of CA1 neurons stabilized after even a brief (6 to 8 weeks) suppression of transgenice tau (SantaCruz et al., 1995).

Behavioral:

Note: These phenotypes are associated with a compound genotype created using this strain: Tg(Camk2a-tTA)1Mmay/? Tg(tetO-MAPT*P301L)#Kha/? (see Double-Cross entry). No significant abnormalities were observed during probe trials in the Morris Water Maze in 1.3 month old mice. However, the maze did reveal spatial memory impairments by 2.5 to 4 months. No significant deficits in motor function were observed up to 6 months of age. When the transgene was suppressed with doxycycline in 2.5 month old mice that had displayed deficits in retention of spatial memory, the mice performed better on the Morris Water Maze by several measures (SantaCruz et al., 1995).

Availability

The Jackson Lab . Under Development. Accepting orders for estimated distribution in March 2012. Stock Number: 015815. Use by companies or for-profit entities requires a license prior to shipping.

Patents:

References

Primary:

SantaCruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A, Deture M, Ramsden M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005 Jul 15;309(5733):476-81. Abstract.