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
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).
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).
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). Expression of the mutant human tau is fivefold higher than that of the endogenous mouse protein (Yoshiyama et al., 2007).
B6N.Cg-Tg(Prnp-MAPT*P301S)PS19Vle/J The Jackson Lab: Stock# 024841; Cryopreserved
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem and spinal cord at six months with progressive accumulation (Yoshiyama et al., 2007).
Neuron loss in the hippocampus and entorhinal cortex by nine to12 months, as well as in the amygdala and neocortex becoming more severe by 12 months (Yoshiyama et al., 2007).
Microgliosis at three months, especially in the white matter of the brain and spinal cord. Increased microgliosis by six months in white and gray matter of the hippocampus, amygdala, entorhinal cortex, and spinal cord. Microglial activation precedes astrogliosis (Yoshiyama et al., 2007).
Synaptophysin immunoreactivity decreased progressively from three to six months in the CA3 region of the hippocamus. Impaired synaptic function (Yoshiyama et al., 2007).
Changes in LTP/LTD
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. bioRxiv preprint first posted online Dec. 18, 2017
- Brunden KR, Zhang B, Carroll J, Yao Y, Potuzak JS, Hogan AM, Iba M, James MJ, Xie SX, Ballatore C, Smith AB, Lee VM, Trojanowski JQ. Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci. 2010 Oct 13;30(41):13861-6. PubMed.
- Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011 Sep 14;31(37):13110-7. PubMed.
- Lasagna-Reeves CA, de Haro M, Hao S, Park J, Rousseaux MW, Al-Ramahi I, Jafar-Nejad P, Vilanova-Velez L, See L, De Maio A, Nitschke L, Wu Z, Troncoso JC, Westbrook TF, Tang J, Botas J, Zoghbi HY. Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. Neuron. 2016 Oct 19;92(2):407-418. Epub 2016 Oct 6 PubMed.