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Saito T, Mihira N, Matsuba Y, Sasaguri H, Hashimoto S, Narasimhan S, Zhang B, Murayama S, Higuchi M, Lee VM, Trojanowski JQ, Saido TC. Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation. J Biol Chem. 2019 Aug 23;294(34):12754-12765. Epub 2019 Jul 4 PubMed.
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University College London
We applaud this careful genetic and phenotypic analysis of the rTg4510 model and encourage similarly comprehensive investigations of other widely used mouse lines. Along this line, we recently demonstrated that in the hAPP-J20 mouse model, the transgene array is inserted into intron one of the Zbtb20 gene, causing a deletion of ~41kb of intronic sequence. Studies are in progress to determine whether this genetic alteration contributes in any way to the phenotype of this model.
It is likely that the genomes of other transgenic mouse models used in dementia research are also altered by transgene insertions. Depending on how they were constructed, even knockout and knock-in models can have genomic alterations that could contribute to their phenotype, for example, through the inadvertent deletion of noncoding RNAs.
We therefore strongly encourage all researchers to undertake a full genetic characterization of their lines, including determining the integration site(s) of all transgenes and the careful analysis of all DNA sequences that were deleted or modified in any way.
Tosh JL, Rickman M, Rhymes E, Norona FE, Clayton E, Mucke L, Isaacs AM, Fisher EM, Wiseman FK. The integration site of the APP transgene in the J20 mouse model of Alzheimer's disease. Wellcome Open Res. 2017;2:84. Epub 2018 Oct 10 PubMed.View all comments by Lennart Mucke
RIKEN Center for Brain Science
The overexpression paradigm is less problematic for modeling tauopathy than for Aβ amyloidosis because limited proteolysis is not a prerequisite for physiological and pathological processing of tau protein. Overexpression of APP results in overproduction of APP, APPsβ, CTFβ, Aβ, AICD, APPsα, CTFα, p3 fragment, APPsη, CTFη, Aη-β and Aη-α, where Aβ is the major component of plaques.
It is probably important to note that most anti-Aβ antibodies bind to CTFβ and APPsα. This requires a caution in interpreting the effect of immunotherapy on the APP-transgenic mice and of human subjects.View all comments by Takaomi Saido
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