reMYND’s APP[V717I] x TAU[P301L] model

reMYND’s proprietary APPxTAU model is combining the progressive amyloidosis and tau-o-pathies modeled by the respective single transgenics, and as such modeling a combined, progressive Abeta and tau pathology.

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, deficit in long term potentiation (LTP) and cognitive impairment.

reMYND's APPxTAU model
Summary

Model

Key Characteristics

APP[V717I] x TAU [P301L]

  • Combined and progressive Abeta and Tau pathology
  • Amyloid accumulation starts intracellularly at young age and is progressively replaced by extracellular amyloid plaques and eventual vascular depositions, and both timing of onset as well as degree, density and distribution do not considerably defer from the single APP[V717I] model
  • Neutral tangles and neuropil treads (=dystrophic neurites) develop in the brainstem, midbrain, cortex and at a later age hippocampus which is not observed in the single TAU[P301L] mouse. Their diffuse respectively highly fibrilar aspects show remarkable resemblance with those seen in Alzheimer patients
  • A cognitive deficit and impaired LTP is observed, followed by progressive weight loss and a motor deficit allowing for a longtitudinal follow-up
Terwel et al., AJP, 2008

In the combined model, expression of the human APP-london and Tau.P301L transgenes is driven by the neuron-specific mouse Thy-1 promoter. The progressive Abeta pathology is observed in hippocampus, cortex and amygdala whereas the Tau pathology is observed in the brainstem, midbrain, cortex and at later age hippocampus (Figure 1). These animals exhibit first a cognitive deficit and impaired LTP, followed by a motor deficit allowing for a longitudinal follow-up. The bigenic APPxTAU model is a useful tool to assess the effects of drug candidates on both the Abeta and Tau pathology in the same model. 

Quantified Methoxy-X04 and AT100 staining of 6-13 month old APP-ld x Tau.P301L animals (n = 8-10 per group (6-12 mo) and n = 3 for 13 mo) in a specified area of the frontal cortex.
Figure 1: Quantified Methoxy-X04 and AT100 staining of 6-13 month old APP-ld x Tau.P301L animals (n = 8-10 per group (6-12 mo) and n = 3 for 13 mo) in a specified area of the frontal cortex.

A confidential data package on reMYND’s APP[V717I]xTAU[P301L] model can be obtained upon request. Hereto, and for all other inquiries please contact Bart Roucourt, Manager CRO.

Reference:
[1] 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).