Posted 10 December 2005

General Information

Transgene: Use system of activator and responder transgenes. Mice expressing activator transgenes (gift of Dr. E. Kandel) were backcrossed 5 times onto 129S6 strain). An activator transgene consisted of the tet-off open reading frame placed downstream of Ca2+-calmodulin kinase II promoter elements, which resulted in expression from the TRE that was restricted to forebrain structures.A responder transgene was generated consisting of a tetracycline operon-responsive element (TRE) placed upstream of a cDNA encoding human four-repeat tau with the P301L mutation (4R0N tauP301L). Mice were bred to generate bigenic progeny containing both transgenes and tg tau mRNA expression in bigenic mice was largely restricted to structures in the forebrain.

Mutation: Tau P301L

Promoter: Ca2+ calmodulin kinase II promoter system, tetracycline-operon responsive element (TRE)

Mouse Strain: Origin: Activator transgene mice on 129S6, backcross 5 timesResponder transgene mice (Tau P301L) on FVB/N

Phenotype

Neuropathological Analysis:

Relevant model of AD and FTDP-17 neurodegeneration. High level of transgene expression (~13U) obtained with fewer responder transgene copies. Mice expressing a repressible human tau variant developed progressive age-related NFTs, and neuronal loss and severe forebrain atrophy. Suppression of tg tau (with Doxycycline), memory function recovered, and neuron numbers stabilized, but NFTs continued to accumulate. Tau mRNA expression in bigenic mice was primarily restricted to structures in the forebrain and predominantly restricted to neuronal cell types.

Behavioral:

Spatial defects observed at 2.5 months and increased with age. Significant cognitive impairments from 4 months of age. oFrom 9.5 months of age, the most severely affected rTg(tauP301L)4510 mice exhibited decreased ambulation and body weight and developed a hunched posture with hind-limb dysfunction and tail rigor. Surprisingly, rTg(tauP301L)4510 mice continued to age, with the oldest living mice currently >20 months of age.

Availability

Dr. Susan Stoddard
Mayo Medical Ventures
Rochester, Minnesota
Email: sstoddard@mayo.edu

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 aneurodegenerative mouse model improves memory function. Science 309(5733): 476-481, 2005 Abstract.

Associated:

Ramsden M, Kotilinek L, Forster C, Paulson J, McGowan E, SantaCruz K, Guimaraes A, Yue M, Lewis J, Carlson G, Hutton M, Ashe KH. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J Neurosci. 2005 Nov 16;25(46):10637-47. Abstract.