Posted 10 December 2005
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
Mouse Strain: Origin: Activator transgene mice on 129S6, backcross 5 timesResponder
transgene mice (Tau P301L) on FVB/N
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.
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.
Dr. Susan Stoddard
Mayo Medical Ventures
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
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.