Research Models

Tau P301L

Synonyms: Tau.P301L, hTau.P301L, Tau-4R-P301L, Tau(P301L)

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Species: Mouse
Genes: MAPT
Mutations: MAPT P301L
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: Thy1-hTau.P301L
Genetic Background: FVB/N
Availability: Available through reMYND.

Neuropathology

Tau hyperphosphorylation and conformational changes in the brain parenchyma start around seven months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex (Terwel et al., 2005). Age-dependent increase in total tau measured in the cerebral spinal fluid (personal communication, reMYND).

Cognition/Behavior

Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014). However, at young ages (eight to ten weeks), Tau P301L mice actually outperform wild-type littermates in object recognition memory (Boekhoorn et al., 2006). The mice also develop progressive motor impairment and inactivity, accompanied by increased clasping of hind and then forelimbs around seven months (Terwel et al., 2005).

Other Phenotypes

Premature death, attributed to hindbrain tauopathy, generally occurs between eight and 12 months (Dutschmann et al., 2010). Premature death is preceded by weight loss, hyperkyphosis, reduced activity, and upper airway dysfunction. At a young age (eight to ten weeks), Tau P301L mice have enhanced long-term potentiation in the dentate gyrus. This is before hyperphosphorylation and tauopathy are apparent (Boekhoorn et al., 2006), and may be due to acclerated dendritic spine maturation (Kremer et al., 2011).

Modification Details

These transgenic mice overexpress human tau, specifically the 4R/2N isoform, bearing the P301L mutation under the control of the neuron-specific murine Thy1 promoter (Terwel et al., 2005).

Availability

Available through the contract research organization reMYND (CRO@remynd.com).

Phenotype Timeline

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Observed

Absent

  • Plaques

Unknown

  • Neuronal Loss
  • Synaptic Loss

Plaques

Absent.

Tangles

Hyperphosphylation, conformational changes, and aggregation of tau resulting in tangle-like pathology by 8 months.

Neuronal Loss

Unknown.

Gliosis

Astrogliosis by 7 months.

Synaptic Loss

Unknown at advanced age. Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).

Changes in LTP/LTD

Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).

Cognitive Impairment

Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).

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References

Paper Citations

  1. . Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem. 2005 Feb 4;280(5):3963-73. PubMed.
  2. . Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopathy. PLoS One. 2014;9(2):e87605. Epub 2014 Feb 3 PubMed.
  3. . Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006 Mar 29;26(13):3514-23. PubMed.
  4. . Upper airway dysfunction of Tau-P301L mice correlates with tauopathy in midbrain and ponto-medullary brainstem nuclei. J Neurosci. 2010 Feb 3;30(5):1810-21. PubMed.
  5. . Early improved and late defective cognition is reflected by dendritic spines in Tau.P301L mice. J Neurosci. 2011 Dec 7;31(49):18036-47. PubMed.

Other Citations

  1. (CRO@remynd.com).

External Citations

  1. reMYND

Further Reading

Papers

  1. . Synaptic dysfunction in hippocampus of transgenic mouse models of Alzheimer's disease: a multi-electrode array study. Neurobiol Dis. 2011 Dec;44(3):284-91. PubMed.