Mutations: MAPT P301L
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: FVB-Tg(tetO-MAPT*P301L)#Kha/JlwsJ, STOCK Tg(Camk2a-tTA)1Mmay Tg(tetO-MAPT*P301L)#Kha/J
Genetic Background: FVB/N
Availability: The Jackson Lab: Stock# 015815 (single transgenic line); Live; The Jackson Lab: Stock# 024854 (double transgenic line); In Progress
These mice express a repressible form of human tau containing the P301L mutation that has been linked with familial frontotemporal dementia (FTD). The transgene can be temporally regulated with the tetracycline analog doxycycline (dox). These mice have been bred to mice containing an activator transgene consisting of a tet-off open reading frame downstream of CAMKII promoter elements. The data described here refer to the bitransgenic progeny which express regulatable tau largely restricted to the forebrain. These bitransgenic mice express approximately 13 units of transgene (one unit is equivalent to the level of endogenous murine tau) and develop progressive age-related neurofibrillary tangles, neuronal loss, and behavioral impairments. Notably, after the transgene was switched off with dox, neuronal death ceased and the ability to acquire and retain new spatial memories was restored (SantaCruz et al., 2005).
The transgene encodes human MAPT with four microtubule binding domains and lacking amino terminal inserts (i.e. 4R0N) with the P301L mutation. Expression is driven by a tetracycline operator (tetO) upstream of a cytomegalovirus minimal promoter and contains exons 2-3 of the mouse prion protein gene (Prnp) untranslated sequence.
Argyrophilic tangle-like inclusions in cortex by four months and in hippocampus by 5.5 months. Decreased CA1 neurons (approximately 60 percent) by 5.5 months. Gross forebrain atrophy by ten months. The number of CA1 neurons stabilized after a brief (six to eight weeks) suppression of transgenic tau.
No significant abnormalities at 1.3 months in the Morris Water Maze. Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to six months. When the transgene was suppressed with dox at 2.5 months spatial memory improved.
Homozygous mice are not viable.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Pretangles as early as 2.5 months. Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months (SantaCruz et al., 2005).
Decreased (~60%) CA1 hippocampal neurons by 5.5 months with significant loss in brain weight. Progressive loss of neurons and brain weight in 7 and 8.5 month mice with ~23% of CA1 pyramidal cells remaining at 8.5 months. Gross atrophy of the forebrain by 10 months (SantaCruz et al., 2005).
Significant loss of dendritic spines at 8-9 months (~30% decrease in spine density in somatosensory cortex)).
No significant abnormalities at 1.3 months but the retention of spatial memory examined by Morris Water Maze became impaired from 2.5 to 4 months. No significant motor impairments up to 6 months. Spatial memory improved when transgene suppressed by dox (SantaCruz et al., 2005).
- 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. PubMed.
- Kopeikina KJ, Wegmann S, Pitstick R, Carlson GA, Bacskai BJ, Betensky RA, Hyman BT, Spires-Jones TL. Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy. PLoS One. 2013;8(11) Epub 2013 Nov 20 PubMed.
- Bailey RM, Howard J, Knight J, Sahara N, Dickson DW, Lewis J. Effects of the C57BL/6 strain background on tauopathy progression in the rTg4510 mouse model. Mol Neurodegener. 2014 Jan 15;9 PubMed.