Mutations: MAPT P301S
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: Thy1-hTau.P301S (CBA.C57BL/6)
Genetic Background: CBAxC57BL/6
Availability: Available at the CRO reMYND
This transgenic model of tauopathy expresses MAPT with the P301S mutation, which is associated with autosomal-dominant disease in humans. The hTau.P301S model recapitulates several molecular, cellular, and behavioral features of human tauopathy, including tau hyperphosphorylation, tau filament formation, neurodegeneration, and motor impairment. Neuropathologically, these mice exhibit widespread tau pathology, affecting the cerebral cortex, hippocampus, brain stem, and spinal cord. In the spinal cord, tau pathology leads to a dramatic loss of motor neurons (approximately 50 percent), and an early, progressive, and severe motor impairment. In homozygous mice, partial paralysis of the lower limbs (paraparesis) develops by 5 to 6 months of age (Allen et al., 2002).
In addition to motor neuron loss, these mice also lose superficial cortical neurons. The number of NeuN-positive cortical neurons was comparable to wild-type at 2 months of age, but transgenic mice had fewer neurons than wild-type at 3 and 5 months of age (Hampton et al., 2011). No neuronal loss was detected in the hippocampus between 2 and 6 months of age (Xu et al., 2014).
These mice develop age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tangle-like pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. They exhibit neurodegeneration, especially loss of motor neurons in the spinal cord, with some loss of superficial cortical neurons. Astrocytosis and microgliosis are also observed. In the hippocampus, a decrease in spine density and spine length has been observed starting at 2.5 months of age (Xu et al., 2014).
Early motor impairment is a prominent phenotype, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. These deficits progress to severe paraparesis. Disinhibition and hyperactivity have been reported at 2 to 3 months of age.
Homozygous mice develop deficits in hippocampal-dependent visuospatial memory as assessed by the Morris water maze. Learning/memory deficits were reported starting at 2.5 months of age, therefore preceding the locomotor deficits in the open field and rotarod tests (Xu et al., 2014); however, a cognitive deficit was not observed at 2 months of age (Scattoni et al., 2010).
Muscle weakness and tremor are observed as well as frequent eye inflammation.
These transgenic mice express a human tau isoform that is 383 amino acids long, with four microtubule-binding repeat domains and no N-terminal inserts (4R/0N). Site-directed mutagenesis was used to introduce the P301S mutation. The transgene is under the control of the neuron-specific murine Thy-1 promoter.
Available at the CRO reMYND.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Neurofibrillary tangles detected as early as 4 months of age.
Neuronal loss starting at 3 months. Loss is especially prominent in the spinal cord with notable loss of superficial cortical neurons as well (Hampton et al., 2010).
Astrocytosis, as measured by GFAP reactivity, in 6 month-old animals. Microglial activation in the brain stem and spinal cord of 5 month-old animals by OX42 staining (Bellucci et al., 2004).
Changes in LTP/LTD
Memory deficit starting at 2.5 months as assessed by the Morris water maze (Xu et al., 2014), but no deficit at 2 months (Scattoni et al., 2010).
- Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci. 2002 Nov 1;22(21):9340-51. PubMed.
- Hampton DW, Webber DJ, Bilican B, Goedert M, Spillantini MG, Chandran S. Cell-mediated neuroprotection in a mouse model of human tauopathy. J Neurosci. 2010 Jul 28;30(30):9973-83. PubMed.
- Xu H, Rösler TW, Carlsson T, de Andrade A, Bruch J, Höllerhage M, Oertel WH, Höglinger GU. Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice. Neuropathol Appl Neurobiol. 2014 Dec;40(7):833-43. PubMed.
- Scattoni ML, Gasparini L, Alleva E, Goedert M, Calamandrei G, Spillantini MG. Early behavioural markers of disease in P301S tau transgenic mice. Behav Brain Res. 2010 Mar 17;208(1):250-7. PubMed.
- Bellucci A, Westwood AJ, Ingram E, Casamenti F, Goedert M, Spillantini MG. Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein. Am J Pathol. 2004 Nov;165(5):1643-52. PubMed.
- Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, Buckner N, Hanmer J, Davies P, O'Neill MJ, Hutton ML, Citron M. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011 Sep 30;286(39):34457-67. PubMed.
- Ozcelik S, Fraser G, Castets P, Schaeffer V, Skachokova Z, Breu K, Clavaguera F, Sinnreich M, Kappos L, Goedert M, Tolnay M, Winkler DT. Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. PLoS One. 2013;8(5):e62459. PubMed.
- Delobel P, Lavenir I, Fraser G, Ingram E, Holzer M, Ghetti B, Spillantini MG, Crowther RA, Goedert M. Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy. Am J Pathol. 2008 Jan;172(1):123-31. PubMed.
- Gasparini L, Crowther RA, Martin KR, Berg N, Coleman M, Goedert M, Spillantini MG. Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability. Neurobiol Aging. 2011 Mar;32(3):419-33. PubMed.