Species: Mouse
Genes: MAPT
Mutations: MAPT P301S
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J
Genetic Background: (C57BL/6 x C3H)F1
Availability: The Jackson Lab: Stock# 008169; Live. Research with this model is available from Scantox Neuro.

Summary

This widely used tauopathy model was developed at the University of Pennsylvania School of Medicine by Virginia Lee, John Trojanowski, and colleagues. As first reported in 2007 on a mixed background, PS19 mice develop neuronal loss and brain atrophy by eight months, principally in the hippocampus but spreading to other brain regions, including the neocortex and entorhinal cortex. They develop widespread neurofibrillary tangle-like inclusions in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Tangle pathology is accompanied by microgliosis and astrocytosis, but not amyloid plaques (Yoshiyama et al., 2007).

Expression of the mutant human tau is fivefold higher than that of the endogenous mouse protein (Yoshiyama et al., 2007).

Prior to the appearance of overt tau pathology by histological methods, the brains of these mice were shown to display tau seeding activity. That is, tau aggregates present in brain homogenate can elicit further tau aggregation, presumably via a prion-like mechanism. Seeding activity was first detected at 1.5 months of age in these mice, indicating that proteopathic tau seeding is an early phenotype in this model (Holmes et al., 2014).

Behaviorally, PS19 mice display signs of age-associated cognitive impairment, including selective deficits in spatial learning and memory ability in the Morris water maze (Takeuchi et al., 2011). Other age-associated behavioral abnormalities include clasping and limb retraction when lifted by the tail, followed by limb weakness. These motor deficits progress to paralysis at seven to 10 months, associated with a hunched-back posture and feeding difficulties. Approximately 80 percent mortality occurs by 12 months in the mixed-background mice, with median survival of about nine months (Yoshiyama et al., 2007).

Recently, some reports have indicated a delay in the onset of pathology in mixed-background PS19 mice. This delay has been reported in mice maintained at the University of Pennsylvania (e.g. Zhang et al., 2012; Iba et al., 2013), but does not appear to affect the Jackson Lab colony at this time (see comment by Mike Sasner below).

Originally bred on a mixed background, PS19 mice have now been backcrossed with C57BL/6J to generate a congenic line (see Related Strains, below). Although not yet as thoroughly characterized as the mixed-background mice, the congenics also show tangle pathology and neuronal loss. They develop neurofibrillary tangle-like inclusions in the brain stem and spinal cord starting around six months of age. Neuronal loss is observed later, around nine months, notably in the hippocampus and brain stem (Maruyama et al, 2013). They also exhibit impaired spontaneous alternation behavior in a Y-maze memory task, increased hyperactivity and decreased anxiety-like behavior, increased pre-pulse inhibition (startle response), and decreased thermal nociceptive threshold (Takeuchi et al., 2011).

Modification Details

PS19 transgenic mice express mutant human microtubule-associated protein tau, MAPT, driven by the mouse prion protein (Prnp) promoter. The transgene encodes the disease-associated P301S mutation and includes four microtubule-binding domains and one N-terminal insert (4R/1N). The transgene inserted at Chr3:140354280-140603283 (Build GRCm38/mm10), causing a 249 Kb deletion that does not affect any known genes (Goodwin et al., 2017).

Related Strains

B6N.Cg-Tg(Prnp-MAPT*P301S)PS19Vle/J The Jackson Lab: Stock# 024841; Cryopreserved

Phenotype Characterization

COMMENTS / QUESTIONS

1. • Michael Sasner
     The Jackson Lab
   • Posted: 14 Aug 2014

   As of August 2014, we have not seen evidence of the phenotypic drift (later onset of symptoms) in the Jackson Laboratory colony as was reported by Dr. Virginia Lee's lab (Iba et al., 2013).

   References:

   Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013 Jan 16;33(3):1024-37. PubMed. Correction.

   View all comments by Michael Sasner

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References

Paper Citations

1. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.
2. Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):E4376-85. Epub 2014 Sep 26 PubMed.
3. Takeuchi H, Iba M, Inoue H, Higuchi M, Takao K, Tsukita K, Karatsu Y, Iwamoto Y, Miyakawa T, Suhara T, Trojanowski JQ, Lee VM, Takahashi R. P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS One. 2011;6(6):e21050. PubMed.
4. Zhang B, Carroll J, Trojanowski JQ, Yao Y, Iba M, Potuzak JS, Hogan AM, Xie SX, Ballatore C, Smith AB, Lee VM, Brunden KR. The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice. J Neurosci. 2012 Mar 14;32(11):3601-11. PubMed.
5. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013 Jan 16;33(3):1024-37. PubMed. Correction.
6. Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, Zhang MR, Trojanowski JQ, Lee VM, Ono M, Masamoto K, Takano H, Sahara N, Iwata N, Okamura N, Furumoto S, Kudo Y, Chang Q, Saido TC, Takashima A, Lewis J, Jang MK, Aoki I, Ito H, Higuchi M. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013 Sep 18;79(6):1094-108. PubMed.
7. 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. bioRχiv preprint first posted online Dec. 18, 2017

External Citations

1. The Jackson Lab: Stock# 024841
2. The Jackson Lab: Stock# 008169
3. Scantox Neuro

Further Reading