Mutations: MAPT K280del
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: N/A
Genetic Background: Unknown.
This tauopathy model expresses regulatable mutant human tau in the forebrain. The transgene encodes full-length tau, specifically the isoform with two N-terminal domains and four microtubule-binding repeat domains (2N4R). The transgene carries a mutation associated with frontotemporal dementia, K280del, a trinucleotide deletion resulting in tau protein with one missing amino acid, a lysine at position 280. In vitro, this mutation strongly promotes tau aggregation (Barghorn et al., 2000); likewise, TauΔK280 mice exhibit extensive pre-tangle pathology, although mature tangles are rarely observed. This model uses the TET-OFF system: Human tau is expressed constitutively, but can be turned off by administering the tetracycline analogue doxycycline. This system has many advantages, especially providing temporal control over transgene expression, thus enabling transgene suppression during development and the ability to investigate the potential reversibility of phenotypes. However, the TET-OFF system also comes with some important caveats (see below).
TauΔK280 mice express relatively low levels of human tau in the brain, approximately one- to threefold higher than endogenous mouse tau. Due to the use of the CAMKIIα promoter, expression is largely restricted to the forebrain, with the highest levels in the hippocampus, cortex, striatum, and olfactory bulb (Eckermann et al., 2007). Due to the relatively low transgene expression, mature tangles are rare in TauΔK280 mice, although some Gallyas silver-positive tangles were observed in very old mice (e.g., older than 24 months). However, extensive pre-tangle tau pathology was observed, including mislocalization of tau out of axons and into cell bodies and dendrites, as well as conformational changes consistent with aggregation, and hyperphosphorylation at a variety of epitopes. Notably, the pre-tangle pathology was shown to be reversible following suppression of the transgene for six weeks.
Expression of the mutant tau does not cause overt neuronal loss in the brain, even after 16 months. However, the mice lose synapses in the hippocampus (CA1, CA3, dentate gyrus). Levels of pre- and postsynaptic proteins are reduced, and electron microscopy show fewer dendritic spines (Van der Jeugd et al., 2012). The loss of spines was confirmed in cultured hippocampal slices. Slices from the mutant mice also showed a modest reduction in ATP compared to slices from non-Tg mice (Dennissen et al., 2016).
The brains of TauΔK280 mice show functional deficits in hippocampal circuits. Hippocampal LTP was impaired when induced by theta burst stimulation. Specifically, post-tetanic potentiation (PTP) was reduced. LTP was also severely impaired in mossy fibers leading from the dentate gyrus to CA3. Basal synaptic transmission of the Schaffer collateral–CA1 pathway was intact (Van der Jeugd et al., 2012).
Behaviorally, TauΔK280 mice have been shown to develop cognitive impairments by 16 months of transgene expression. Deficits were seen in paradigms that test spatial learning/memory as well as contextual learning. TauΔK280 mice took longer to find the hidden platform in the Morris water maze than non-Tg controls. In addition, TauΔK280 mice failed to associate a mild foot shock with entering a dark compartment. Grip strength, Rotarod performance, and overall activity levels were normal (Van der Jeugd et al., 2012).
Models employing the TET-OFF system, such as the TauΔK280 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 tTa effects. For example, certain backgrounds (e.g., C3HeJ and CBA) may be more susceptible to tTA-mediated neurodegeneration, whereas the C57BL/6J background appears more resistant. For reasons that are not yet clear, tTA-mediated neurodegeneration can be largely circumvented by postnatal doxycycline for six weeks. The TauΔK280 phenotypes described here were observed using this doxcycline protocol, making it unlikely that the pathology was due to tTA itself. This conclusion is supported by the fact that a second regulatable tau transgenic, reported in parallel and carrying mutations that impair tau aggregation, did not develop appreciable tau pathology despite expressing tTA.
All phenotype data described on this page refer to observations in hemizygous mice.
These are bigenic mice in which the TET-OFF system is used to provide temporal control of human tau expression in the brain. Tetracycline transactivator (tTA) is downstream of the CAMKIIα promoter, driving expression in excitatory neurons in the forebrain. tTA in turn stimulates expression of the responder transgene, full-length human tau (hTau40, 2N4R) carrying the FTD-associated deletion ΔK280. Transgene expression can be repressed with doxycycline.
TauRDΔK280 (“Proaggregation mutant”): This model also expresses regulatable human tau carrying the ΔK280 mutation, however, the human tau sequence expressed is not full-length, but an abbreviated sequence (amino acids 244-372) encompassing the four microtubule-binding repeat domains, hence the "RD" in the model's name. Like the TauΔK280 model, the TauRDΔK280 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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
Mature tangles are observed only at advanced age (>24 months), but extensive pre-tangle pathology develops with as little as three months of transgene expression. This includes mislocalization of tau to the somatodendritic compartment, conformational changes indicative of aggregation, and hyperphosphorylation (e.g. Ser 262, Ser 356).
Electron microscopy showed a moderate decrease in spine synapses in the CA1 region of the hippocampus following 13 months of gene expression.
Changes in LTP/LTD
Impaired hippocampal LTP in the CA1 and CA3 areas.
Cognitive deficits in the Morris water maze and in passive-avoidance paradigms.
Last Updated: 14 Oct 2016
Research Models Citations
- Barghorn S, Zheng-Fischhöfer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. PubMed.
- Eckermann K, Mocanu MM, Khlistunova I, Biernat J, Nissen A, Hofmann A, Schönig K, Bujard H, Haemisch A, Mandelkow E, Zhou L, Rune G, Mandelkow EM. 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.
- Van der Jeugd A, Hochgräfe K, Ahmed T, Decker JM, Sydow A, Hofmann A, Wu D, Messing L, Balschun D, D'Hooge R, Mandelkow EM. Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau. Acta Neuropathol. 2012 Jun;123(6):787-805. PubMed.
- Dennissen FJ, Anglada-Huguet M, Sydow A, Mandelkow E, Mandelkow EM. Adenosine A1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11597-11602. Epub 2016 Sep 26 PubMed.
- Han HJ, Allen CC, Buchovecky CM, Yetman MJ, Born HA, Marin MA, Rodgers SP, Song BJ, Lu HC, Justice MJ, Probst FJ, Jankowsky JL. Strain background influences neurotoxicity and behavioral abnormalities in mice expressing the tetracycline transactivator. J Neurosci. 2012 Aug 1;32(31):10574-86. PubMed.
- Liu P, Paulson JB, Forster CL, Shapiro SL, Ashe KH, Zahs KR. 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.