Species: Mouse
Genes: MAPT
Mutations: MAPT P301L
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: 129S6.Cg-Tg(Camk2a-tTA)1Mmay/JlwsJ; Fgf14^{Tg(tetO-MAPT*P301L)4510Kha}/J. Formerly: 129S6.Cg-Tg(Camk2a-tTA)1Mmay/JlwsJ; FVB-Tg(tetO-MAPT*P301L)#Kha/JlwsJ
Genetic Background: Mixed: 129S6 (activator) X FVB (responder)
Availability: 4510 responder line: The Jackson Lab: Stock# 015815; Activator line: The Jackson Lab: Stock# 016198.

Summary

rTg4510 mice express a repressible form of human tau containing the P301L mutation that has been linked with familial frontotemporal dementia. Since its initial description in 2005 (Ramsden et al., 2005; Santacruz et al., 2005), this mouse has become a popular model, as it phenocopies the tau pathology and pronounced neurodegeneration observed in human tauopathies, in addition to providing researchers with temporal control over mutant tau transgene expression. However, a 2019 study showed that disruption of an endogenous mouse gene, caused by random insertion of the MAPT^P301L transgene, significantly contributes to the neuropathological and neurodegenerative phenotypes observed in rTg4510 mice (Gamache et al., 2019). Researchers are thus urged to be cautious in ascribing findings in these mice to the expression of transgenic tau^P301L.

rTg4510 mice (“r” for regulatable) are produced by crossing the 4510 responder line, carrying a human MAPT^P301L cDNA downstream of a tetracycline operon–responsive element (TRE), to an activator line expressing a tetracycline-controlled transactivator (tTA) under control of the CaMKIIα promoter. Bi-transgenic progeny constitutively express human tau^P301L until transgene expression is inactivated by administration of the tetracycline analog doxycycline (dox). Transgene expression is largely restricted to the forebrain by the CaMKIIα promoter.

The integration sites of the CaMKIIα-tTA and MAPT^P301L transgenes have been mapped, and both transgenes were found to disrupt endogenous mouse genes (Gamache et al., 2019; Goodwin et al., 2019). The CaMKIIα-tTA transgene inserted on chromosome 12, resulting in a 508 kb deletion that affects five mouse genes: Vipr2 (vasoactive intestinal peptide receptor 2), Wdr60 (WD repeat-containing protein 60), Esyt2 (extended synaptotagmin-like protein 2), Ncapg2 (non-SMC condensin II complex, subunit G2), and Ptprn2 (protein tyrosine phosphatase, receptor type, N polypeptide 2). The integration site of the MAPT^P301L transgene is within the Fgf14 (fibroblast growth factor 14) gene on chromosome 14, resulting in a 244 Kb deletion that includes exon 1.

In order to dissect the effects of tau^P301L over expression and Fgf14 disruption, a second line of responder mice, called “T2” was employed (Gamache et al., 2019). To create T2 mice, a targeted insertion strategy was used to place the MAPT^P301L transgene in a location in the mouse genome where no endogenous mouse genes would be disrupted. T2 mice were then crossed with the CaMKIIα-tTA activator line to create bi-transgenic mice (designated rT2/T2 when homozygous for the MAPT^P301L transgene). rT2/T2 mice express even more tau^P301L than rTg4510 mice, yet neurodegeneration is delayed and tau pathology occurs later and is less extreme in rT2/T2 mice than in rTg4510 mice. These findings indicate that disruption of Fgf14 contributes to the neuropathological and neurodegenerative phenotypes observed in rTg4510 mice.

In addition, shrinkage of the dentate gyrus occurs in the CaMKIIα-tTA activator line, although it is not yet known whether this is due to the expression of tTA or to the disruption of one or more endogenous mouse genes. This phenotype has been seen in some, but not all, genetic backgrounds (Han et al., 2012), including hybrid 129S6 X FVB (Liu et al., 2015; Helboe et al., 2017).

Keeping in mind the caveat that not all phenotypes in rTg4510 mice are necessarily due to tau^P301L overexpression, the following summarizes the extensive literature describing rTg4510 mice.

rTg4510 mice express high levels of mutant tau (approximately 13 times the level of endogenous murine tau), and they develop progressive age-related neurofibrillary tangles, neuronal loss, and behavioral impairments (Ramsden et al., 2005). Notably, following transgene suppression with dox, neuronal death ceases and decline in cognitive function is arrested or even reversed (SantaCruz et al., 2005; Spires et al., 2006; Blackmore et al., 2017).

Gender differences have been reported, with females displaying more aggressive tau pathology and more severe behavioral deficits than males (Yue, et al., 2011; Song et al., 2015).

Neuropathology | Electrophysiological properties | Cognition/Behavior | Modification details | Note | Availability

Neuropathology

The bi-transgenic mice accumulate an early burden of tau pathology in the form of argyrophilic tangle-like inclusions. These tangles are observed in the cortex by 4 months of age and in the hippocampus by 5.5 months (Ramsden et al., 2005; SantaCruz et al., 2005). Suppression of transgenic tau^P301L expression from conception through six weeks of age has been reported to delay the onset of tau pathology for up to six months (Helboe et al., 2017).

rTg4510 mice develop neuronal loss, although the timing and extent may vary between laboratories (e.g., one group reported an approximate 60 percent decrease in hippocampal CA1 neurons by about 5.5 months (Ramsden et al., 2005; SantaCruz et al., 2005), while a second group found a 43 percent decrease between 8 and 12 months (Helboe et al., 2017)). Cortical cell loss occurs slightly later, at about 8. 5 months of age (Spires et al., 2006), and gross forebrain atrophy is observed by 10 months. Brain-weight loss was found to correlate with body-weight loss (Helboe et al., 2017). Suppression of transgenic tau^P301L protects against neurodegeneration in this model: the number of CA1 neurons stabilized after six to eight weeks of suppression, while longer suppression (dox treatment from 5.5 to 9 months of age) resulted in preservation of brain weight (SantaCruz et al., 2005).

Synaptic density, assessed immunohistologically, is similar in bi-transgenic rTg4510 and single-transgenic CaMKIIα-tTA and Tg4510 mice at 8.5 months, while in vivo imaging revealed dendritic spine loss in 9.5 month rTg4510 mice (Kopeikina et al., 2013). Levels of pre- and post-synaptic proteins decrease beginning between 24 and 48 weeks of age (Helboe et al., 2017).

White matter pathology is also present in rTg4510 mice.  Atrophy of the dorsal corticospinal tracts was observed in sections of the spinal cord in 10-month mice (Ramsden et al., 2005).  In vivo, diffusion tensor imaging revealed lower fractional anisotropy values in white matter tracts in 8.5 month rTg4510 mice compared with non-transgenic animals (Sahara et al., 2014). Electron microscopy showed swollen, degenerating axons and disrupted myelin sheaths (Ludvigson et al., 2011; Sahara et al., 2014).

Gliosis, in the form of increased immunoreactivity for the astrocyte marker GFAP and the microglial marker Iba1, was seen at 2.5 months of age (Helboe et al., 2017).

Electrophysiological properties

In vitro, rTg4510 cortical neurons display elevated resting membrane potentials and hyperexcitability.  These changes occur independently of NFT pathology, being found in neurons from mice as young as 1-3 months of age, prior to tangle formation, and in both tangle-bearing and tangle-free neurons in older mice (Rocher et al., 2010; Crimins et al., 2012). However, resting potentials in cortical neurons did not differ between rTg4510 and non-transgenic mice recorded in vivo in anesthetized animals, and reduced activity of the neocortical network was shown in freely behaving mice at 5 months of age (Menkes-Caspi et al., 2015).

Hippocampal plasticity, recorded in vitro, is disrupted in an age-dependent manner. LTP at the Schaffer collateral-CA1 synapse is normal at 1.3 months, but impaired at 4.5 months (Hoover et al., 2010), while a deficit in paired-pulse facilitation appears between 3 and 6 months (Gelman et al., 2018). In vivo, place coding of CA1 neurons is disrupted: CA1 neurons in freely-moving 7-9 month rTg4510 displayed a stereotypical firing sequence unrelated to location in space, in contrast to neurons in non-transgenic animals, where neuronal activity was tied to location (Cheng and Ji, 2013).

Cognition/Behavior

rTg4510 mice display age-dependent deficits in a variety of cognitive and behavioral tests.

In the Morris water maze, deficits in spatial navigation are seen as early as 1.3 months of age (Ramsden et al., 2005), while spatial memory deficits appear between 2.5 and 4 months (Ramsden et al., 2005; Yue, et al., 2011). Females are more severely impaired than males (Yue, et al., 2011). Spatial memory improved when the transgene was suppressed with dox as late as 5.5 months of age (SantaCruz et al., 2005).

Hyperactivity in the open-field test has been observed as early as 2 months of age, in a study of female mice (Wes et al., 2014). A study that pooled data from both genders reported hyperactivity at 6 months but not at 2 months (Cook et al., 2014). A third study reported hyperactivity by 4 months in male mice, the earliest age examined (Blackmore et al., 2017). Studies that compare male and female animals in the same laboratory under the same experimental conditions are needed to determine whether there are gender differences in the age of onset or severity of this behavioral abnormality.

Deficits in novel object recognition appear between 2 and 4 months of age in bi-transgenic rTg4510 mice (Wes et al., 2014; Blackmore et al., 2017). However, similar deficits occur in single transgenic CaMKIIα-tTA mice (Wes et al., 2014), implying that deficits in this task may be related to the presence of tTA and not to tau pathology.

Compared with non-transgenic mice, rTg4510 mice display deficits in contextual fear conditioning by 2 months of age, while deficits in cued fear conditioning appear between 2 and 6 months (Cook et al., 2014).

Motor function in rTg4510 mice appears normal at 6 months (SantaCruz et al., 2005), but by 10 months, mice exhibit clasping and limb retraction when lifted by the tail, and dystonic posture with tail rigor (Ramsden et al., 2005).  Nonetheless, mice perform normally on the Rotarod at 12 months (Blackmore et al., 2017).

Differences between rTg4510 and non-transgenic mice have been reported in additional behavioral tests, including the Y-maze test of spatial working memory (Wes et al., 2014), the swim escape Y-maze test of spatial reference memory (Blackmore et al., 2017), and the elevated plus maze test of anxiety (Cook et al., 2014).

Modification Details

The MAPT^301L transgene encodes human tau with four microtubule binding domains and lacking amino terminal inserts (4R/0N), with the P301L mutation. Expression is driven by a tetracycline operator upstream of a cytomegalovirus minimal promoter. The transgene also contains exons 2-3 of the mouse prion protein gene (Prnp) untranslated sequence.

The CaMKIIα-tTA transgene contains the tetracycline-controlled transactivator protein (tTA) under control of the forebrain-specific calcium/calmodulin-dependent kinase II promoter.

Note

Homozygous mice are not viable.

There are minor differences in the levels of tau^P301L expression and phosphorylation in rTg4510 on a C57BL/6 X FVB background compared with 129S6 X FVB, but behavioral and neurodegenerative phenotypes do not differ (Bailey et al., 2014).

Availability

The 4510 responder line (Stock# 015815) is available through Jackson Laboratories, which also offers activator lines on three different genetic backgrounds: 129S6 (Stock# 016198), used in the originally described rTg4510 mice (Ramsden et al., 2005; SantaCruz et al., 2005), C57BL/6 (Stock# 007004), and FVB (Stock# 025105). Bi-transgenic rTg4510 mice on a C57BL/6 (activator) X FVB (responder) background are also available from The Jackson Lab: Stock# 024854. Research services with rTg4510 are available from the CRO PsychoGenics.

Phenotype Characterization

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References

Paper Citations

1. 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. PubMed.
2. 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.
3. Gamache J, Benzow K, Forster C, Kemper L, Hlynialuk C, Furrow E, Ashe KH, Koob MD. Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice. Nat Commun. 2019 Jun 6;10(1):2479. PubMed.
4. Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. Genome Res. 2019 Mar;29(3):494-505. Epub 2019 Jan 18 PubMed.
5. Han HJ, Allen CC, Buchovecky CM, Yetman MJ, Born HA, Marin MA, Rodgers SP, Song BJ, Lu HC, Justice MJ, Probst FJ, Jankowsky JL. Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator. J Neurosci. 2012 Aug 1;32(31):10574-86. PubMed.
6. Liu P, Paulson JB, Forster CL, Shapiro SL, Ashe KH, Zahs KR. Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique β-Amyloid Oligomer Profile. PLoS One. 2015;10(5):e0126317. Epub 2015 May 6 PubMed.
7. Helboe L, Egebjerg J, Barkholt P, Volbracht C. Early depletion of CA1 neurons and late neurodegeneration in a mouse tauopathy model. Brain Res. 2017 Jun 15;1665:22-35. Epub 2017 Apr 11 PubMed.
8. Spires TL, Orne JD, Santacruz K, Pitstick R, Carlson GA, Ashe KH, Hyman BT. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol. 2006 May;168(5):1598-607. PubMed.
9. Blackmore T, Meftah S, Murray TK, Craig PJ, Blockeel A, Phillips K, Eastwood B, O'Neill MJ, Marston H, Ahmed Z, Gilmour G, Gastambide F. Tracking progressive pathological and functional decline in the rTg4510 mouse model of tauopathy. Alzheimers Res Ther. 2017 Sep 20;9(1):77. PubMed.
10. Yue M, Hanna A, Wilson J, Roder H, Janus C. Sex difference in pathology and memory decline in rTg4510 mouse model of tauopathy. Neurobiol Aging. 2011 Apr;32(4):590-603. Epub 2009 May 7 PubMed.
11. Song L, Lu SX, Ouyang X, Melchor J, Lee J, Terracina G, Wang X, Hyde L, Hess JF, Parker EM, Zhang L. Analysis of tau post-translational modifications in rTg4510 mice, a model of tau pathology. Mol Neurodegener. 2015 Mar 26;10:14. PubMed.
12. Kopeikina KJ, Polydoro M, Tai HC, Yaeger E, Carlson GA, Pitstick R, Hyman BT, Spires-Jones TL. Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol. 2013 Apr 15;521(6):1334-53. PubMed.
13. Sahara N, Perez PD, Lin WL, Dickson DW, Ren Y, Zeng H, Lewis J, Febo M. Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study. Neurobiol Aging. 2014 Jun;35(6):1364-74. Epub 2013 Dec 19 PubMed.
14. Ludvigson AE, Luebke JI, Lewis J, Peters A. Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy: a light and electron microscopy study. Brain Struct Funct. 2011 Mar;216(1):31-42. PubMed.
15. Rocher AB, Crimins JL, Amatrudo JM, Kinson MS, Todd-Brown MA, Lewis J, Luebke JI. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol. 2010 Jun;223(2):385-93. PubMed.
16. Crimins JL, Rocher AB, Luebke JI. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol. 2012 Dec;124(6):777-95. PubMed.
17. Menkes-Caspi N, Yamin HG, Kellner V, Spires-Jones TL, Cohen D, Stern EA. Pathological tau disrupts ongoing network activity. Neuron. 2015 Mar 4;85(5):959-66. Epub 2015 Feb 19 PubMed.
18. Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Pitstick R, Carlson GA, Lanier LM, Yuan LL, Ashe KH, Liao D. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.
19. Gelman S, Palma J, Tombaugh G, Ghavami A. Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer's Disease. J Alzheimers Dis. 2018;61(1):195-208. PubMed.
20. Cheng J, Ji D. Rigid firing sequences undermine spatial memory codes in a neurodegenerative mouse model. Elife. 2013;2:e00647. PubMed.
21. Wes PD, Easton A, Corradi J, Barten DM, Devidze N, DeCarr LB, Truong A, He A, Barrezueta NX, Polson C, Bourin C, Flynn ME, Keenan S, Lidge R, Meredith J, Natale J, Sankaranarayanan S, Cadelina GW, Albright CF, Cacace AM. Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease. PLoS One. 2014;9(8):e106050. Epub 2014 Aug 25 PubMed.
22. Cook C, Dunmore JH, Murray ME, Scheffel K, Shukoor N, Tong J, Castanedes-Casey M, Phillips V, Rousseau L, Penuliar MS, Kurti A, Dickson DW, Petrucelli L, Fryer JD. Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol Aging. 2014 Jul;35(7):1769-77. Epub 2013 Dec 26 PubMed.
23. 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;9:8. PubMed.

External Citations

1. Stock# 015815
2. Stock# 016198
3. Stock# 007004
4. Stock# 025105
5. Stock# 024854
6. PsychoGenics
7. The Jackson Lab: Stock# 015815
8. The Jackson Lab: Stock# 016198

Further Reading