Tau transgenic Mouse Models

Experts in the field have debated for decades whether amyloid-beta or tau is the better target to cure Alzheimer’s Disease. We cannot answer this question but we can offer an extensive CRO service with transgenic mouse models for both aspects of the disease.

TMHT transgenic Mouse Model

The TMHT (Thy1 Mutated Human Tau) mouse was developed in-house and is exclusively available at QPS Neuropharmacology. These animals represent a suitable model not only for Alzheimer’s disease but also for other tauopathies such as Frontotemporal Dementia and Parkinsonism linked to chromosome 17 (FTDP-17).
Various compounds of different classes were positively tested for their efficacy in the TMHT model. Published examples are the γ-secretase modulator CHF5074 (Lanzilotta 2010), sodium selenate (Corcoran et al., 2010) and grape-seed polyphenol extract (Wang et al., 2010).
TMHT mice express the longest human tau isoform Tau441 (2N4R) with two mutations, V337M and R406W, under regulatory control of the neuron-specific murine Thy1 promoter. Mice are bred on a C57BL/6 background. The human tau overexpression leads to high levels of soluble and sarcosyl insoluble tau in the brain that progressively increase. Furthermore, animal develop learning ad memory deficits.

Figure 1: Phosphorylated tau at Thr231 in the hippocampus of 3-13 months old TMHT mice. Mean + SEM; n = 10. Two-way ANOVA with Bonferroni`s post hoc test. ***p<0.001.
Figure 2: Morris water maze test of 5 months old TMHT mice. Escape latency (A) and abidance in the target quadrant (B). Mean ± SEM, n = 7. A: Two-way ANOVA with Bonferroni`s post hoc test. B: Unpaired t-test.

hTau transgenic Mouse Model

hTau mice express human tau derived from a human PAC, H1 haplotype, known as 8c mice, while murine tau is knocked out by a targeted disruption of exon 1. Animals express all 6 human tau isoforms and present with accumulations of phosphorylated tau, aggregated tau and PHFs.

Figure 1: Quantitative analysis of ptau Ser202 (A) and Ser396 (B) level in the cortex of 3 and 12 month old hTau mice compared to non-transgenic littermates. Immunoreactive area in percent. n = 8 per group. Mean + SEM; Two-way ANOVA with Bonferroni’s post hoc test; ***p<0.001. Similar results were observed for hippocampal ptau Ser202 and ptau Ser396.

Soluble total and phosphorylated tau levels in the brain of hTau mice. Soluble tissue fractions of 3, 6, 9, and 12 month old animals were analyzed for total, pThr231 and pThr181 levels by MSD immunosorbent assay. One-way ANOVA with Newman’s Keuls multiple comparison test. Mean ± SEM; n = 2-4.

PS19 transgenic Mouse Model

The PS19 transgenic mouse expresses the T34 isoform and 4 microtubule binding repeats (1N4R) of the tau protein with P301S mutation under the regulatory control of the murine prion promoter (Prnp). PS19 mice are a popular model to study tau aggregation, tauopathy and other symptoms of Alzheimer`s disease (University of Pennsylvania, USA; JAX 008169; Yoshiyama et al., 2007).

 

Animals present the following phenotype:

  • Neuronal accumulation of phosphorylated tau and paired helical filaments (PHF) in different brain regions at 6 months (Yoshiyama et al., 2007)
  • Cerebral atrophy and neuron loss at 12 months (Yoshiyama et al., 2007)
  • Neuroinflammation observed as activated microglia and astrocytosis at 6 months and older (Yoshiyama et al., 2007; Lopez-Gonzalez et al., 2015)
  • Muscle weakness and neurogenic muscular atrophy at 3 months (Yoshiyama et al., 2007)
  • Reduced anxiety at 9 months (Briggs et al., 2017)
  • Learning and memory deficits at 9 months (Briggs et al., 2017)
  • Reduced survival (Yoshiyama et al., 2007)

 

Results from published efficacy studies show that many of these symptoms are partly reversible by different compounds:

  • Survival, nueroinflammation, tau phosphorylation (Yoshiyama et al., 2007)
  • Axonal dystrophy, learning an memory (Brunden et al., 2010)
  • Brain atrophy, survival, nest building (DeVos et al., 2017)

 

The phenotype described above, relevant for AD and other neurodegenerative disorder, makes the PS19 mouse a perfect model for your drug testing.

QPS Neuropharmacology offers custom tailored study design for these models and we are flexible to accommodate to your special interests. We are also happy to advice you and propose study designs. QPS Neuropharmacology maintains its own colonies directly in our research facility. Non-transgenic littermates are available as control animals needed for proper study design.
We would be happy to test your compounds in these mouse models! Readouts depend on model but the most common are:

  • Total tau and phosphorylated tau at different residues
  • Learning and memory deficits (MWM)
  • Looking for something else? Please contact us!

You might be also interested in these related models

As with all other in vivo models we are also ready to provide samples (brain tissue, CSF etc.) from these animals for analyses in your laboratory.

We are happy to receive your inquiry.

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