Research Models

TauRDΔK280 (“Proaggregation mutant”)

Synonyms: TauRDΔ, TauRD, TauRD/ΔK280, TauRDΔK

Species: Mouse
Genes: MAPT
Mutations: MAPT K280del
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: C57BL/6
Availability: Unknown

Summary

This tauopathy model expresses a region of human tau in the forebrain that can be turned off with the tetracycline analog doxycycline. The transgene is not full-length tau, but an abbreviated sequence, encoding the four microtubule-binding repeat domains of the human protein. Because it is regulatable, the transgene can be suppressed until maturity to avoid potential developmental effects, and it can be switched off at any time to investigate the reversibility of observed phenotypes. These mice develop a number of neuropathological and behavioral features reminiscent of AD and FTD, including neurofibrillary tangles, neuronal loss, and cognitive deficits.

These mice express a relatively low amount of exogenous tau, about 70 percent of mouse tau protein. Expression is somewhat variable, so regularly checking expression levels is recommended (see Sydow et al., 2011). The transgene includes the K280del mutation, a deletion mutation that strongly promotes tau aggregation in vitro (Barghorn et al., 2000). Similar pro-aggregation effects occur in vivo; the mutant transgene spurs aggregation of exogenous and endogenous tau into paired helical filaments and Gallyas silver-positive tangles. Tangles are detected after as little as two to three months of transgene expression, beginning in the entorhinal cortex and related limbic areas, and later spreading to the neocortex. Aggregation is accompanied by tau hyperphosphorylation and mislocalization of the protein into the somato-dendritic compartment, and away from axons (Mocanu et al., 2008). 

Neuronal loss develops in specific regions of the hippocampus, notably the dentate gyrus, with as little as five months of transgene expression (Mocanu et al., 2008). Although the transgene is expressed throughout the forebrain, the mossy fiber pathway in the hippocampus is particularly sensitive to the mutant tau as reflected in structural changes at the mossy fiber/CA3 synapse and measures of plasticity, including impaired long-term depression, long-term potentiation, and synaptic transmission (Sydow et al., 2011). These effects are attributed to structural changes at the synapse, disrupted local calcium signaling, and depletion of synaptic vesicles (Decker et al., 2015).

These mice display learning and memory deficits as assessed by the Morris water maze and passive avoidance test after 10 months of transgene expression. At this age, gross motor function was largely intact, with normal grip strength and spontaneous activity, and just slightly reduced performance on the Rotarod (Sydow et al., 2011).

Notably, many of the phenotypes described above were shown to be reversible following transgene suppression for a period of time. For example, in the paradigm in which the transgene was expressed postnatally for 10 months and then turned off for four months, cognitive function rebounded, as did LTP. Synapse number partially recovered, along with other synaptic markers. However, neuronal loss and tau aggregates persisted, although the latter became comprised almost exclusively of endogenous mouse tau (Mocanu et al., 2008Sydow et al., 2011).

Models employing the TET-OFF system, such as the TauRDΔK280 model, come with the caveat that the expression of tTA itself can cause a number of phenotypes relevant to the study of neurodegenerative disease, including decreased forebrain weight, loss of hippocampal neurons, and behavioral deficits (Han et al., 2012; Liu et al., 2015). This means that "tTA only" littermates are an important control when using tTA to drive a transgene of interest. The selection of genetic background may also minimize non-specific effects of tTA. For example, certain backgrounds (e.g. C3HeJ and CBA) may be more susceptible to tTA-mediated neurodegeneration, whereas the C57BL/6J background (the background of the TauRDΔK280 model), appears more resistant (Han et al., 2012).

All data described on this page refer to results in hemizygous TauRDΔK280 mice.

Modification Details

This model enables regulatable expression of an abbreviated human tau sequence (amino acids 244-372) encompassing the four microtubule-binding repeat domains and carrying the ΔK280 mutation. The transgene is driven by the forebrain-specific CAMKIIα promoter. This model uses a TET-OFF system in which the transgene is activated by the tetracycline controlled transactivator (tTA) and can be turned off by administration of doxycycline.

Related Strains

TauΔK280 ("Proaggregation mutant")- This model also expresses regulatable human tau carrying the ΔK280 mutation, however full-length protein is expressed (2N4R), rather than an abbreviated sequence. Like the TauRDΔK280 model, the TauΔK280 model uses a TET-OFF system to regulate transgene expression, employing the CAMKIIα promoter to drive tTA expression in forebrain neurons and subsequent activation of the tau transgene.

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

  • Plaques

No Data

Neuronal Loss

Neuronal loss in the dentate gyrus (granule neurons) following 5 months of transgene expression. Shrinkage of the molecular layer of the hippocampus.

Plaques

Absent.

Tangles

Tau tangles and aggregates with as little as 2-3 months of transgene expression. Tangles start in the entorhinal cortex and amygdala and spread to the neocortex by 15 months. Heterogeneous tangle morphology, including flame-shaped.

Gliosis

Astrogliosis in the hilus region of the hippocampus after 21 months of transgene expression. Additional increases in GFAP-positive astrocytes in the entorhinal and piriform cortices.

Synaptic Loss

Hippocampal synaptic loss as indicated by multiple measures following 9.5 months of transgene expression. Reduced synaptophysin immunoreactivity and reduced number of spine synapses as measured by electron microscopy.

Changes in LTP/LTD

Multiple deficits in synaptic plasticity, including deficits in LTP and LTD, after 10 months of transgene expression. Functional changes are associated with structural synaptic changes, local calcium dysregulation, and a decrease in the synaptic vesicle pool.

Cognitive Impairment

Learning and memory impairments are apparent after 10 months of transgene expression as assessed by the Morris water maze and passive avoidance tasks.

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References

Research Models Citations

  1. TauΔK280 ("Proaggregation mutant")

Paper Citations

  1. . Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci. 2011 Feb 16;31(7):2511-25. PubMed.
  2. . Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. PubMed.
  3. . The potential for beta-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy. J Neurosci. 2008 Jan 16;28(3):737-48. PubMed.
  4. . Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca++ dysregulation. Acta Neuropathol Commun. 2015 Apr 3;3(1):23. PubMed.
  5. . Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator. J Neurosci. 2012 Aug 1;32(31):10574-86. PubMed.
  6. . Characterization of a Novel Mouse Model of Alzheimer's Disease--Amyloid Pathology and Unique β-Amyloid Oligomer Profile. PLoS One. 2015;10(5):e0126317. Epub 2015 May 6 PubMed.

Further Reading

Papers

  1. . Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model. J Mol Neurosci. 2011 Nov;45(3):432-7. PubMed.
  2. . The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy. J Biol Chem. 2007 Oct 26;282(43):31755-65. Epub 2007 Aug 23 PubMed.
  3. . Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator. J Neurosci. 2012 Aug 1;32(31):10574-86. PubMed.