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.
The TMHT (Thy-1 Mutated Human Tau) mouse was developed in-house and is exclusively available at QPS Austria.
Many years of experience with this model gave us the opportunity to extensively test the model in internal validation studies and also in contract research studies for our customers. 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: Tau levels||Figure 2: MWM|
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 significantly increased swim length and escape latency. Learning curves in MWM are by far not as steep as in non-transgenic littermates. (Figure 2)
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.
|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
The translational value of preclinical studies in Tau transgenic mouse models to human trials is intensely discussed. Of special interest in that regard, is certainly the Morris water Maze test for memory, since there highly comparable cognitive test exist for humans. Another aspect comes from recently performed histological comparisons of Tau pathology in human AD samples and samples from TMHT mice that revealed remarkable similarities.
QPS Austria offers custom tailored study design for this model 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 latency. Compared to other Tau transgenic mouse lines, the TMHT line shows relevant features of Tauopathies already at young age. This allows for extraordinarily fast turn-around times. Further direct 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 model! 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
• Looking for something else? Please contact us!
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
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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.
Flunkert S., Hierzer M., Löffler T., Rabl R., Neddens J. , Duller S., Schofield E.L., Ward M.A., Posch M., Windisch M., Hutter-Paier B. Elevated levels of soluble total and phosphorylated Tau result in early behavioural deficits and distinct changes of brain pathology in a new Tau transgenic mouse model. Neurodegener Dis. 2012;
Lanzilotta et al., The γ-Secretase Modulator CHF5074 Reduces the Accumulation of Native Hyperphosphorylated Tau in a Transgenic Mouse Model of Alzheimer's Disease. J Mol Neurosci. 2010 Dec 22. [Epub ahead of print].
Corcoran et al., Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model. J Clin Neurosci. 2010 Aug;17(8):1025-33. Epub 2010 May 26.
Wang, J., Santa-Maria, I., Ho, L., Ksiezak-Reding, H., Ono, K., Teplow, D.B., Pasinetti,G.M., 2010. Grape derived polyphenols attenuate tau neuropathology in a mousemodel of Alzheimer’s disease. Journal of Alzheimer’s Disease: JAD 22, 653–661.
Windisch M, Flunkert S, Havas D, Hutter-Paier B. Commentary to the recently published review "Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease" by Li, Evrahimi and Schluesener. Ageing Res. Rev. 2013 Jan;12(1):116-40. Ageing Res Rev. 2013 Jul 10;12(4):852-854. doi:10.1016/j.arr.2013.06.006. [Epub ahead of print] PubMed PMID: 23851053.