Research Models

SHR72

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 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, SHR318, 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).

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 reported to be 0.95-, 0.6-, 2.4-, and 0.9- fold those of endogenous rat tau, in cortex, hippocampus, brainstem, and spinal cord, respectively (Valachova et al., 2018). It should be noted that the level of transgenic tau in the brainstem was reported to be higher—7.5 times that of endogenous tau—in an earlier study (Koson et al., 2008). The reason for this inter-study variability is unknown.

SHR72 rats have a shorter lifespan than wild-type SHR rats. The mean lifespan of SHR72 rats is 217 days, with the oldest animal living to 289 days (Koson et al., 2008). Non-transgenic SHR rats normally live 22 to 24 months.

Neuropathology

Neurofibrillary tangles, demonstrated by Gallyas silver stain, were found the brainstems and spinal cords of terminal-stage (7- to 8-month old) animals (Stozicka et al., 2010). Additional pathological features present at this time included somatodendritic mislocalization of tau (Zilka et al., 2010); immunoreactivity for monoclonal antibody AT8, which recognizes tau phosphorylated at both serine 202 and threonine 205 (Koson et al., 2008; Valachova et al., 2018); and immunoreactivity for the conformation-dependent antibody DC11 (Valachova et al., 2018, 29633258). Tau pathology was most pronounced in the gigantocellular reticular nucleus (GRN) of the brainstem, where approximately 11 percent of neurons were AT8-positive (Koson et al., 2008).

Although neuron loss has not been documented, there is evidence of neurodegeneration in SHR72 rats. Chromatolytic neurons and damaged axons were seen in the brains of 7-month animals, particularly in the brainstem reticular formation (Zilka et al., 2010). Stereological analysis of neuron numbers in the GRN and hippocampi revealed similar numbers of neurons in 7.5-month male transgenic and non-transgenic animals (Koson et al., 2008). However, female transgenic rats had fewer neurons than male transgenics; since non-transgenic females were not studied, whether the lower neuron numbers in female SHR72 rats reflect normal gender differences or gender-specific pathology is not known.

Microgliosis and astrogliosis were seen in the brains of terminally staged SHR72 rats, in regions with neurofibrillary pathology and axon damage (Stozicka et al., 2010).

Norepinephrine levels, measured in 6-month males, were reduced in forebrain structures innervated by the locus coeruleus, including the hippocampus and frontal and temporal cortices (Mravec et al., 2016).

Behavior

When rats were evaluated using a custom battery of neurobehavioral tests, two stages of impairment were identified (Zilka et al., 2010). Beginning at about 3 months of age, animals were considered to display “mild neurobehavioral impairment”—they had difficulty traversing a balance beam, showed hind-limb clasping in the tail-suspension test, and forelimb muscle-strength began to wane. This stage lasted about three months, and then rats experienced a rapid, dramatic decline. Animals showing “severe behavioral impairment” could no longer traverse a balance beam, displayed pronounced hind-limb clasping and loss of muscle strength, and failed a series of neurological reflex tests (placing, righting, postural, pinna, and startle). This represented a terminal stage lasting several days until animals succumbed.

Biomarkers

Levels of neurofilament light chain were elevated in the cerebrospinal fluid (CSF) of 5- to 7-month SHR72 rats, compared with non-transgenic controls (Majerova et al., 2017). In a longitudinal study, average levels of CSF p-tau181 (tau phosphorylated at threonine 181) more than doubled as animals transitioned from mild to severe neurobehavioral impairment (Zilka et al., 2010).

Related Strains

WKY72. This line carries the truncated human tau transgene on a Wistar-Kyoto background. The line was created by back-crossing the SHR72 line to Wistar-Kyoto rats for at least five generations (Stozicka et al., 2010). Levels of transgene expression are identical in WKY72 and SHR72 rats. However, at terminal stages, WKY72 rats have approximately 1.6-fold fewer neurofibrillary tangle-bearing neurons than SHR72 rats, and the two lines differ with regards to microglial characteristics.

Modification Details

SHR72 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
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

Neurofibrillary tangles, demonstrated by Gallyas silver stain, are present in the brainstem and spinal cord.

Neuronal Loss

Although neuron loss has not been documented, chromatolytic neurons and damaged axons were seen in the brains of 7-month animals, particularly in the brainstem reticular formation.

Gliosis

Astrogliosis and microgliosis are present in brainstem regions bearing neurofibrillary tangles.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

Sensorimotor deficits and abnormal reflexes observed as early as 3 months, but no data available from cognitive tests.

Last Updated: 07 Jun 2019

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References

Research Models Citations

  1. SHR318
  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. . 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. . 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.
  8. . Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease. J Neuroinflammation. 2010;7:64. PubMed.
  9. . CSF phospho-tau correlates with behavioural decline and brain insoluble phospho-tau levels in a rat model of tauopathy. Acta Neuropathol. 2010 Jun;119(6):679-87. PubMed.
  10. . Tauopathy in transgenic (SHR72) rats impairs function of central noradrenergic system and promotes neuroinflammation. J Neuroinflammation. 2016 Jan 20;13:15. PubMed.
  11. . Changes of Cerebrospinal Fluid Peptides due to Tauopathy. J Alzheimers Dis. 2017;58(2):507-520. PubMed.

Further Reading

No Available Further Reading