Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease
Strain Name: B6.Cg-Tg(Thy-MAPT*)2652Gds
Genetic Background: C57BL/6J
Availability: The MMRRC Stock# MMRRC:036717

Summary

In contrast to the lion’s share of tauopathy models, this transgenic overexpresses wild-type human tau rather than mutant tau. Therefore, it may be especially well-suited for modeling sporadic tauopathy. This model may have particular relevance to early stage disease, because the mice develop widespread pretangle pathology at a young age, but the phenotype does not progress to mature neurofibrillary tangles or neuronal loss (Wheeler et al., 2015). Behaviorally, these mice show deficits in muscle strength, as well as in spatial learning and memory.

The human tau expressed by these mice is the most abundant isoform in the brain, consisting of one N-terminal domain (1N) and all four microtubule binding repeat domains (4R). Tau4RTg2652 mice exhibit approximately 12-fold overexpression transgenic tau in the brain relative to endogenous murine tau. Despite these high protein levels, neurofibrillary tangle pathology is absent even at advanced age (e.g., 24 months). Likewise oligomeric tau, as assessed by the TOC1 antibody, which selectively labels tau dimers and oligomers, was minimal and restricted to the CA1 region of the hippocampus. In contrast, Tau4RTg2652 mice develop widespread pretangle pathology from a young age. By 3 months of age, phosphorylated tau is observed in neurons of the cortex, hippocampus, amygdala, brainstem, and spinal cord, as indicated by the AT8 antibody. Tau pathology did not accumulate beyond 3 months, indicating minimal progression with age.

In addition to high levels of phospho-tau, dystrophic neurites were observed throughout the brain especially in the striatum and cortex. Dilated axons, spheroids immunoreactive for p-tau, were also noted in the cortex, striatum, hindbrain, and spinal cord.

Behaviorally, Tau4RTg2652 mice show motor deficits, including decreased performance on tests of grip strength. They also have slightly reduced motor coordination as measured by performance on the accelerating Rotarod. In addition to these mild motor problems, Tau4RTg2652 mice show cognitive deficits, including decreased performance in the Barnes maze, indicative of impaired spatial learning and memory.

Both homo- and hemizygous mice are viable. However, homozygous mice have reduced body weight, more severe motor abnormalities, reduced fertility, and premature death. A number of homozygous mice also exhibit seizure activity. Hemizygous mice have a normal lifespan.

Modification Details

This transgenic mouse overexpresses wild-type human tau (1N4R). The Thy1.2 promoter drives high levels of transgene expression in the CNS.

Phenotype Characterization

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References

Paper Citations

1. Wheeler JM, McMillan PJ, Hawk M, Iba M, Robinson L, Xu GJ, Dombroski BA, Jeong D, Dichter MA, Juul H, Loomis E, Raskind M, Leverenz JB, Trojanowski JQ, Lee VM, Schellenberg GD, Kraemer BC. High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration. Acta Neuropathol Commun. 2015 Jun 4;3:33. PubMed.

External Citations

1. Stock# MMRRC:036717

Further Reading

No Available Further Reading