Tau transgenic Mouse Models
TMHT transgenic Mouse Model
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.
Figure 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
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.
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.
• 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!
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
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• 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.
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.