Species: Mouse
Genes: MAPT
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 for academic use from Michel Goedert and for commercial use from LifeArc. Also available from The Mary Lyon Centre at MRC Harwell, Archive# HAR: 011664. The CRO reMYND offers research services with this line.

Summary

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).

Neuropathology

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).

Cognition/Behavior

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).

Other Phenotypes

Muscle weakness and tremor are observed as well as frequent eye inflammation.

Modification Details

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.

Phenotype Characterization

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References

Paper Citations

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

External Citations

1. Michel Goedert
2. LifeArc
3. The Mary Lyon Centre at MRC Harwell, Archive# HAR: 011664
4. reMYND

Further Reading