reMYND’s TAU[P301L] model and its bigenic combination with APP-London
reMYND’s proprietary TAU[P301L] transgenic, modeling a progressive tau-o-pathy and therefore serving as an excellent model for FTD and Alzheimer’s disease, is now being extended into an APPxTAU model combining both Abeta and tau pathology.
In reMYND’s single TAU[P301L] transgenic mice, hTAU is expressed under control of the mouse Thy-1 promoter. The observed tau conformational change and age-dependent accumulation of AT8 and AT100 reactive insoluble tau have been proposed to trigger an age-dependent tangle pathology (starting at age 8-9 months) ([1], Figure 1A). In parallel, and with a strong correlation in time, the TAU[P301L] mice develop motor deficits like limb clasping and reduced survival, i.e. succumbing before age 12 months [1]. This model has proven very suitable for therapeutic testing of candidate drugs aimed at tau pathology ([1] and unpublished data).
To introduce tau pathology in the APP-London mouse, the bigenic APP[V717I]xTAU[P301L] mouse line (APPxTAU) was created [1, 2]. Three important characteristics of Alzheimer’s disease are recapitulated in this model: intracellular neurofibrillary tangles (NFTs), extracellular amyloid plaques and cognitive impairments. The amyloid pathology in these mice is more intense compared to the single APP-London mouse, but similar in its timing and aspects ([2] and unpublished data). NFT pathology is significantly enhanced in the hippocampus and cortex relative to the parental single TAU[P301L] model, developing in the same time frame as the amyloid plaques ([2], Figure 1B). The bigenic APPxTAU model is highly valuable for investigating the molecular interplay between Abeta and tau in causing neurodegeneration and as a tool to evaluate drug candidates that interfere with one or both aspects of the Alzheimer pathology.
Figure 1. AT100-responsive pathological tau levels (A) in brainstem of 8-month old TAU[P301L] mice, (B) in midbrain of 3-month old APP[V717I]xTAU[P301L] mice.
The table below summarizes the key characteristics of reMYND’s proprietary TAU[P301L] and APP[V717I]xTAU[P301L] Alzheimer transgenic mice, recapitulating important pathological and clinical hallmarks of Alzheimer’s disease and therefore valuable paradigms for evaluating therapeutic candidates.
A confidential data package on reMYND’s TAU[P301L] and APP[V717I]xTAU[P301L] model can be obtained upon request. Please contact Dr. An Tanghe, Manager Contract Research.
A recent paper, entitled ‘Pathological hallmarks, clinical parallels and value for drug testing in Alzheimer's disease of the APP[V717I] London transgenic mouse model’ reviews all key early and late hallmarks of the Alzheimer pathology in this model, and discusses clinical parallels with AD patients and the value of the APP-London transgenic mouse model for preclinical in vivo testing of experimental Alzheimer therapies. The paper also touches on reMYND’s other proprietary mouse models and is freely downloadable here.
For more information, please contact Dr. An Tanghe.
References:
[1] Terwel D, Lasrado R, Snauwaert J, Vandeweert E, Van Haesendonck C, Borghgraef P, Van Leuven F. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, non-lethal axonopathy of Tau-4R/2N transgenic mice, J. Biol. Chem. 280:3963-3973 (2005).
[2] Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, Van Leuven F. Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol. 172(3):786-98 (2008).
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