Research Models

SHR318

Species: Rat
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: SHR
Availability: No longer available.

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. SHR318 rats express a tau fragment truncated at the N- and C-terminals, containing four 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 (Zilka et al., 2006). A second line, SHR72, derived from a different founder expressing the same transgene, has also been developed (Zilka et al., 2006), as has a related strain, SHR24, which expresses truncated tau containing the proline-rich region but three microtubule-binding domains (Filipcik et al., 2012).

Unless stated otherwise, this page describes rats hemizygous for the transgene.

SHR318 rats overexpress human truncated tau in the cortex, hippocampus, diencephalon, brainstem, and spinal cord. Levels of transgenic protein are two- to fivefold those of endogenous rat tau, with the highest levels in brainstem and spinal cord (Zilka et al., 2006; Koson et al., 2008).

SHR318 rats have a shorter lifespan than wild-type SHR rats. The mean lifespan of hemizygous SHR318 rats is 10–12 months and that of homozygotes is five to six months (Zilka et al., 2006). Non-transgenic SHR rats normally live 22–24 months.

Neuropathology

Neurofibrillary tangles (NFTs), demonstrated by Gallyas silver staining, Congo Red birefringence, and Thioflavin S-positivity, first appear at 9 months and are particularly prominent in the brainstem and spinal cord. In the brainstem gigantocellular reticular nucleus (GRN) of 10-month rats, approximately 12 percent of neurons contain tangles (Zilka et al., 2006; Koson et al., 2008). Hyperphosphorylated tau, revealed by immunostaining with monoclonal antibody AT8, is seen in cortical and hippocampal pyramidal neurons, as well as neurons in brainstem regions and spinal cord (Zilka et al., 2006; Hrnkova et al., 2007). The range of AT8-immunoreactive structures appears to reflect the progression from pre-tangles to mature NFTs to extracellular ghost tangles (Zilka et al., 2006).

Neuron numbers in the hippocampi and GRN do not differ between 10.5-month SHR318 rats and non-transgenic rats (Koson et al., 2008).

Axonal degeneration was observed in the brainstems and spinal cords of 10- to 12-month animals (Hrnkova et al., 2007).

Biochemistry

Biochemical methods were also used to examine the aggregation and hyperphosphorylation of tau in the brains of SHR318 rats (Zilka et al., 2006). Filamentous tau aggregates are not soluble in the detergent sarkosyl (Greenberg and Davies, 1990), and levels of sarkosyl-insoluble tau in the brains of SHR318 rats indeed correlated with neurofibrillary pathology. Sarksosyl-insoluble fractions from 3-month-old rats contained only human truncated tau, while fractions from 10- to 12-month rats contained approximately equal amounts of transgenic tau and endogenous rat tau. Hyperphosphorylated tau was present in the sarkosyl-insoluble fractions from SHR318 rats 9 months of age and older. No sarkosyl-insoluble tau was found in brain extracts from non-transgenic rats.

Behavior

Neurological function of male SHR318 rats was evaluated using a battery of tests (Hrnkova et al., 2007). At 4.5 months of age, animals displayed normal learning, but impaired spatial memory, in the Morris water maze. At 7 months, 50 percent of transgenic rats showed an impaired hind-limb escape extension reflex (i.e., rats exhibited hind-limb clasping during the tail-hang test). Additional reflexes (placing, righting) became compromised between 7 and 12 months. At 9 months, sensorimotor coordination was impaired in a balance beam test. SHR318 rats performed similarly to controls in the open field and in a prehensile traction test (horizontal wire-hang) that measures muscle strength and equilibrium. Bradykinesia and paraparesis were observed as animals entered the terminal stage.

Modification Details

SHR318 rats express a gene encoding amino acids 151-391 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

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

Absent

  • Neuronal Loss

No Data

  • Plaques
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

No data.

Tangles

Argyrophilic neurofibrillary tangles are particularly prominent in the brainstem and spinal cord.

Neuronal Loss

Neuron numbers in the hippocampi and brainstem gigantocellular reticular nucleus do not differ between 10.5-month SHR318 rats and non-transgenic rats.

Gliosis

No data.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

At 4.5 months, rats show normal learning, but deficits in spatial memory, in the Morris water maze.

Last Updated: 07 Jun 2019

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References

Research Models Citations

  1. SHR72
  2. SHR24

Paper Citations

  1. . DC11: a novel monoclonal antibody revealing Alzheimer's disease-specific tau epitope. Neuroreport. 2003 Jan 20;14(1):87-91. PubMed.
  2. . 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. . Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423. FEBS Lett. 2004 Jun 18;568(1-3):178-82. PubMed.
  4. . Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo. FEBS Lett. 2006 Jun 26;580(15):3582-8. PubMed.
  5. . First transgenic rat model developing progressive cortical neurofibrillary tangles. Neurobiol Aging. 2012 Jul;33(7):1448-56. Epub 2010 Dec 31 PubMed.
  6. . Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load. Eur J Neurosci. 2008 Jul;28(2):239-46. PubMed.
  7. . Neurodegeneration caused by expression of human truncated tau leads to progressive neurobehavioural impairment in transgenic rats. Brain Res. 2007 Jan 26;1130(1):206-13. PubMed.
  8. . 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