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

Nat Commun. 2019 Jun 6;10(1):2479. doi: 10.1038/s41467-019-10428-1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrophy
  • Disease Models, Animal*
  • Fibroblast Growth Factors / genetics*
  • Mice*
  • Mice, Transgenic
  • Phenotype
  • Prosencephalon / metabolism*
  • Prosencephalon / pathology
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology
  • Tauopathies / genetics*
  • Tauopathies / metabolism
  • Tauopathies / pathology
  • tau Proteins / genetics*

Substances

  • MAPT protein, human
  • fibroblast growth factor 14
  • tau Proteins
  • Fibroblast Growth Factors