Research Models

rTg(tauP301L)4510

Synonyms: rTg4510, Tg(tetO-TauP301L)4510, Tau P301L

Species: Mouse
Genes: MAPT
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 (Double tg also has B6)
Availability: Single transgenic: The Jackson Lab: Stock# 015815; Live. Double transgenic: The Jackson Lab: Stock# 024854; Live. Also available at the CRO PsychoGenics

Summary

The rTg4510 mouse is a versatile tauopathy model providing researchers with temporal and spatial control over mutant tau transgene expression. The mice express a repressible form of human tau containing the P301L mutation that has been linked with familial frontotemporal dementia. The transgene is downstream of a tetracycline operon–responsive element (TRE), and expression is driven by a second transgene containing a tetracycline-controlled transactivator (tTA) under control of a promoter such as CaMKII-α. Tau is constitutively expressed until inactivated by administration of the tetracycline analog doxycycline (dox).

The data described on this page refer to bitransgenic progeny expressing regulatable tau largely restricted to the forebrain by the CaMKII-α promoter. These bitransgenic 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. Notably, following transgene suppression with dox, neuronal death ceased and the ability to acquire and retain new spatial memories was restored (Santacruz et al., 2005).

Neuropathology

The bitransgenic 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. The mice also develop neuronal loss, including about a 60 percent decrease in hippocampal CA1 neurons, by about 5.5 months. The number of CA1 neurons stabilized after a brief (six- to eight-week) suppression of transgenic tau (Santacruz et al., 2005). 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.

Electrophysiological properties of cortical neurons are significantly affected prior to the accumulation of tau pathology. Reduced activity of the neocortical network was shown in freely behaving mice at 5 months of age (Menkes-Caspi et al., 2015). However, recordings from cortical slices have also shown early hyperexcitability (Crimins et al., 2012). Resting membrane potential, action potential firing rates, and other electrophysiological properties are also affected.

Cognition/Behavior

No significant abnormalities are observed early on; mice reportedly navigate the Morris water maze normally at 1.3 months of age. Deficits develop with age, with spatial memory problems becoming apparent by 2.5 to 4 months of age. These mice do not develop significant motor impairment up to 6 months. When the transgene was suppressed with dox at 2.5 months of age, spatial memory improved.

Modification Details

The transgene encodes human MAPT 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 and contains exons 2-3 of the mouse prion protein gene (Prnp) untranslated sequence.

Note

Homozygous mice are not viable.

Availability

The single transgenic is available through The Jackson Lab: Stock# 015815. The double transgenic is also available The Jackson Lab: Stock# 024854 and at the CRO PsychoGenics.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Plaques

No Data

  • Changes in LTP/LTD

Neuronal Loss

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.

Plaques

Absent.

Tangles

Pretangles as early as 2.5 months. Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months.

Synaptic Loss

Significant loss of dendritic spines at 8-9 months (~30% decrease in spine density in somatosensory cortex).

Changes in LTP/LTD

Electrophysiological properties of cortical neurons are altered as early as 1 to 3 months of age. In freely behaving mice, individual neocortical pyramidal neurons are less active as is the neocortical network as a whole. Hyperexcitability of cortical neurons has been observed in vitro, along with effects on resting membrane potential and action potential firing rates.

Cognitive Impairment

No significant abnormalities at 1.3 months but retention of spatial memory (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.

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References

Paper Citations

  1. 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.
  2. 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.
  3. 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.
  4. 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.

External Citations

  1. The Jackson Lab: Stock# 015815
  2. The Jackson Lab: Stock# 024854
  3. PsychoGenics
  4. The Jackson Lab: Stock# 015815
  5. The Jackson Lab: Stock# 024854
  6. PsychoGenics

Further Reading

Papers

  1. 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):e80834. Epub 2013 Nov 20 PubMed.
  2. 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.
  3. Koppel J, Jimenez H, Azose M, D'Abramo C, Acker C, Buthorn J, Greenwald BS, Lewis J, Lesser M, Liu Z, Davies P. Pathogenic tau species drive a psychosis-like phenotype in a mouse model of Alzheimer's disease. Behav Brain Res. 2014 Dec 15;275:27-33. Epub 2014 Aug 20 PubMed.
  4. 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.
  5. 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.
  6. 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.
  7. Crimins JL, Rocher AB, Peters A, Shultz P, Lewis J, Luebke JI. Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy. Acta Neuropathol. 2011 Nov;122(5):551-64. PubMed.
  8. Nash KR, Lee DC, Hunt JB, Morganti JM, Selenica ML, Moran P, Reid P, Brownlow M, Guang-Yu Yang C, Savalia M, Gemma C, Bickford PC, Gordon MN, Morgan D. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol Aging. 2013 Jun;34(6):1540-8. PubMed.
  9. 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. 2012 Oct 10; PubMed.
  10. 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.
  11. Sahara N, Deture M, Ren Y, Ebrahim AS, Kang D, Knight J, Volbracht C, Pedersen JT, Dickson DW, Yen SH, Lewis J. Characteristics of TBS-Extractable Hyperphosphorylated Tau Species: Aggregation Intermediates in rTg4510 Mouse Brain. J Alzheimers Dis. 2012 Aug 31; PubMed.
  12. 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.
  13. 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.
  14. 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.
  15. Weitzner DS, Engler-Chiurazzi EB, Kotilinek LA, Ashe KH, Reed MN. Morris Water Maze Test: Optimization for Mouse Strain and Testing Environment. J Vis Exp. 2015 Jun 22;(100):e52706. PubMed.
  16. Scott L, Kiss T, Kawabe TT, Hajós M. Neuronal network activity in the hippocampus of tau transgenic (Tg4510) mice. Neurobiol Aging. 2016 Jan;37:66-73. Epub 2015 Oct 14 PubMed.
  17. Zhao X, Kotilinek LA, Smith B, Hlynialuk C, Zahs K, Ramsden M, Cleary J, Ashe KH. Caspase-2 cleavage of tau reversibly impairs memory. Nat Med. 2016 Nov;22(11):1268-1276. Epub 2016 Oct 10 PubMed.