Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice

Julia Gamache, Kellie Benzow, Colleen Forster, Lisa Kemper, Chris Hlynialuk, Eva Furrow, Karen H. Ashe () and Michael D. Koob ()
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Julia Gamache: N. Bud Grossman Center for Memory Research and Care
Kellie Benzow: Department of Laboratory Medicine and Pathology
Colleen Forster: BLS Histology and IHC Laboratory
Lisa Kemper: N. Bud Grossman Center for Memory Research and Care
Chris Hlynialuk: N. Bud Grossman Center for Memory Research and Care
Eva Furrow: University of Minnesota
Karen H. Ashe: N. Bud Grossman Center for Memory Research and Care
Michael D. Koob: Department of Laboratory Medicine and Pathology

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The tauopathy-like phenotype observed in the rTg4510 mouse line, in which human tauP301L expression specifically within the forebrain can be temporally controlled, has largely been attributed to high overexpression of mutant human tau in the forebrain region. Unexpectedly, we found that in a different mouse line with a targeted-insertion of the same transgene driven by the same tetracycline-TransActivator (tTA) allele, but with even higher overexpression of tauP301L than rTg4510, atrophy and tau histopathology are delayed, and a different behavioral profile is observed. This suggests that it is not overexpression of mutant human tau alone that contributes to the phenotype in rTg4510 mice. Furthermore we show that the tauopathy-like phenotype seen in rTg4510 requires a ~70-copy tau-transgene insertion in a 244 kb deletion in Fgf14, a ~7-copy tTA-transgene insertion in a 508 kb deletion that disrupts another five genes, in addition to high transgene overexpression. We propose that these additional effects need to be accounted for in any studies using rTg4510.

Date: 2019
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DOI: 10.1038/s41467-019-10428-1

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