Species: Rat
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: SHR
Availability: Unknown.

Summary

Following observations that monoclonal antibodies selective for truncated tau species recognize tau extracted from AD brains (Vechterova et al., 2003) and tau in the core of paired helical filaments (Novak et al., 1993; Skrabana et al., 2004), these transgenic rats were created to study the pathophysiological effects of truncated tau. SHR24 rats express a tau fragment truncated at the N- and C-terminals, containing three microtubule-binding domains and a proline-rich region on an SHR (spontaneously hypertensive rat) background. Expression of the transgene is driven by the mouse Thy1 promoter (Filipcik et al., 2012). Two related lines, SHR72 and SHR318, express truncated tau containing the proline-rich region but four microtubule-binding domains (Zilka et al., 2006).

This page describes rats hemizygous for the transgene.

Transgenic tau is expressed in the brain and spinal cord. Levels of transgenic tau measured in 3-month-old males were found to be 0.5-, 0.8-, 1.2-, and 0.75-fold those of endogenous rat tau, in cortex, hippocampus, brainstem, and spinal cord, respectively (Valachova et al., 2018). Levels were found to be higher in 4-month female rats: 3.5-, 4-, and 2.5 times that of endogenous tau in cortex, hippocampus, and brainstem, respectively (Filipcik et al., 2012). It is unclear whether the differences in protein levels measured in these two studies are due to differences in age or sex of the animals, or whether they reflect inter-study variability.

SHR24 rats have a shorter lifespan than wild-type SHR rats. The mean lifespan of SHR24 rats is 423 days, with the oldest animal living to 475 days (Filipcik et al., 2012). Non-transgenic SHR rats normally live 22 to 24 months.

Neuropathology

Neurofibrillary tangles, demonstrated by Gallyas silver staining, Congo Red birefringence, and Thioflavin S-positivity, accumulate in cortex, hippocampus, thalamus, and brainstem. Tangles first appear at 9 to 10 months, and the number of tangle-bearing neurons increases with age (Filipcik et al., 2012). Prior to the appearance of argyrophilic neurofibrillary tangles, neurons became immunoreactive for antibodies directed against hyperphosphorylated and truncated tau (Valachova et al., 2018).

No neuron loss was observed in the hippocampi or cortices of male rats examined at 15 month of age, near the maximum lifespan for this line (Filipcik et al., 2012). However, decreased levels of synaptophysin and a decreased number of synaptic vesicles per synapse were found in animals of this age (Jadhav et al., 2015).

Biochemistry

Biochemical methods were also used to examine the aggregation and hyperphosphorylation of tau in the brains of SHR24 rats. Filamentous tau aggregates are not soluble in the detergent sarkosyl (Greenberg and Davies, 1990). Sarkosyl-insoluble fractions from 8-month SHR24 rats contained only human truncated tau. In sarkosyl-insoluble fractions from 10-month rats, a portion of the truncated tau was found to be hyperphosphorylated, and this fraction now also included endogenous rat tau. Levels of hyperphosphorylated rat and human tau increased with age through 15 months, the average lifespan of this transgenic line (Filipcik et al., 2012). Among the tau species in the sarkosyl-insoluble fractions from 15-month SHR24 rats were three prominent bands between 55- and 72- kDa, similar to a triplet of bands seen in sarkosyl-insoluble fractions from AD brains (Valachova et al., 2018). Notably, almost no tau was found in sarkosyl-insoluble fractions from non-transgenic rats (Jadhav et al., 2015).

Both transgenic truncated tau and endogenous tau were associated with post-synaptic densities (PSDs) biochemically isolated from aged SHR24 rats; only trace amounts of tau protein were found in PSDs isolated from wild-type rats (Jadhav et al., 2015).

These findings suggest that the presence of truncated human tau leads to the hyperphosphorylation, aggregation, and mislocalization of endogenous rat tau in this model.

Behavior

Male SHR24 rats exhibit age-dependent impairments in several neurobehavioral tests (Valachova et al., 2018). Abnormal hind-limb clasping during the tail-hang test is apparent by 3.5 months of age. At 5 months, SHR24 rats take longer to traverse a cylindrical balance beam, compared with non-transgenic rats, and by 8 months, the transgenic rats are unable to remain on the beam. Postural and spinal reflexes wane and forelimb muscle-strength declines beginning by 7 months of age. SHR24 rats behave similarly to non-transgenic animals in the open field, when tested at 3 to 7 months.

Behavioral data from female rats are not available.

Modification Details

SHR24 rats express a gene encoding amino acids 151-274 and 306-391 of human tau, driven by the mouse Thy1 promoter (the numbering of amino acids corresponds to that of the 441-amino acid isoform of human tau, variously referred to as tau 40, Tau-F, or 2N4R).

Phenotype Characterization

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References

Research Models Citations

1. SHR72
2. SHR318

Paper Citations

1. Vechterova L, Kontsekova E, Zilka N, Ferencik M, Ravid R, Novak M. DC11: a novel monoclonal antibody revealing Alzheimer's disease-specific tau epitope. Neuroreport. 2003 Jan 20;14(1):87-91. PubMed.
2. Novak M, Kabat J, Wischik CM. Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. EMBO J. 1993 Jan;12(1):365-70. PubMed.
3. Skrabana R, Kontsek P, Mederlyova A, Iqbal K, Novak M. Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423. FEBS Lett. 2004 Jun 18;568(1-3):178-82. PubMed.
4. Filipcik P, Zilka N, Bugos O, Kucerak J, Koson P, Novak P, Novak M. First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol Aging. 2012 Jul;33(7):1448-56. Epub 2010 Dec 31 PubMed.
5. Zilka N, Filipcik P, Koson P, Fialova L, Skrabana R, Zilkova M, Rolkova G, Kontsekova E, Novak M. Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 2006 Jun 26;580(15):3582-8. PubMed.
6. Valachova B, Brezovakova V, Bugos O, Jadhav S, Smolek T, Novak P, Zilka N. A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau. J Comp Neurol. 2018 Aug 1;526(11):1777-1789. Epub 2018 Apr 26 PubMed.
7. Jadhav S, Katina S, Kovac A, Kazmerova Z, Novak M, Zilka N. Truncated tau deregulates synaptic markers in rat model for human tauopathy. Front Cell Neurosci. 2015;9:24. Epub 2015 Feb 23 PubMed.
8. Greenberg SG, Davies P. A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5827-31. PubMed.

Further Reading

No Available Further Reading