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 (Thy-1 Mutated Human Tau) mouse was developed in-house and is exclusively available at QPS Austria. 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) and Niemann Pick’s disease.

Various compounds of different classes (among them also antibody treatments) 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 Thy-1 promoter. Mice are bred in our facility on a C57BL/6 background. The human tau overexpression leads to high levels of soluble and sarcosyl insoluble tau in the brain with an age dependant increase (Figure 1).

Figure 1: Hyperphosphorylated tau at Thr231 in the hippocampus of 3-13 months old TMHT mice.

 

 

 

 

Transgenic tau gets hyperphosphorylated at different disease relevant residues. Tau hyperphosphorylation is accompanied by a pronounced memory deficit. Already 5 months old TMHT animals demonstrate spatial learning deficits as shown by a significantly increased swim length and escape latency. Learning curves in the Morris water maze are by far not as steep as in non-transgenic littermates. (Figure 2)

Figure 2: Morris water maze test of 5 months old TMHT mice. Escape latency and abidance in the target quadrants.

 

 

 

 

Importantly, no motor deficits are observed for this model. Further, the TMHT mouse line resembles human AD tau pathology as evaluated by immunohistochemistry. Human tau accumulates mainly in neuronal somata. Especially in the amygdala an age-dependent increase of both ptau and human total tau levels is observed.

Figure3Figure 3: A)  Amygdala with massive intracellular PHF tau load. B) Astrocytosis in amygdala. C) Iba-1 immunoreactive microglia with typically activated shape. D) Cortex: Cells showing neuronal perikaria and neurites (axones and dendrites) massively loaded with tau.

 

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 hyperphosphorylated tau, aggregated tau and PHFs.

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

QPS Austria offers custom tailored study design for this models and we are flexible to accommodate to your special interest. We are also happy to advice you and propose previously successful study designs. A typical turnaround time from agreement to the study plan to the final report is about 4 months. QPS Austria maintains its own colony directly in our research facility. Animals of all age groups are typically available without any long delay. Compared to other tau transgenic mouse models, the TMHT line shows relevant features of tauopathies already at young age. This allows for extraordinarily fast turn-around times. Non-transgenic littermates are available as control animals needed for proper study design.

We would be happy to test your compounds in our tau transgenic mouse models! The most common readouts are:

•    Memory (MWM)
•    Tau and tau phosphorylation (p181, p202, p231, p262, and p396) in brain extracts
•    Tau pathology evaluated by IHC with antibodies HT7 (human tau), Tau-5 (total tau), AT180, 9G3, AT8
•    Looking for something else? Please contact us!

Alternative models

QPS Austria offers alternative models allowing the performance of the same type of studies also in every other commercially available mouse line, e.g. P301L.

You might be also interested in these related topics

•    Tau surrounding plaques in the APP transgenic mouse model
•    Tau phosphorylation in hypothermia mouse model
•    Human tau overexpressing cell line
•    Tau and ptau in human CSF samples

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.