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 through 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 five to six months of age (Allen et al., 2002).
These mice also develop age-related loss of a superficial cortical neurons. Although neuronal loss was not appreciable at two months of age, the number of NeuN-positive neurons was lower at three and five months of age compared with wild-type controls (Hampton et al., 2011).
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.
Early motor impairment is a prominent phenotype, including abnormal clasping and rotarod deficit at four months, with nearly complete deficit at five months. These deficits progress to severe paraparesis. Disinhibition and hyperactivity have been reported at two to three months.
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 in length with 4 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 through 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
- Cognitive Impairment
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
- 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.
- 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.