Developmental pathogenicity of 4-repeat human tau is lost with the P301L mutation in genetically matched tau-transgenic mice

Julia E. Gamache, Lisa Kemper, Elizabeth Steuer, Kailee Leinonen-Wright, Jessica M. Choquette, Chris Hlynialuk, Kellie Benzow, Keith A. Vossel, Weiming Xia, Michael D. Koob, Karen H. Ashe

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Tau is a microtubule-associated protein that becomes dysregulated in a group of neurodegenerative diseases called tauopathies. Differential tau isoforms, expression levels, promoters, and disruption of endogenous genes in transgenic mouse models of tauopathy make it difficult to draw definitive conclusions about the biological role of tau in these models. We addressed this shortcoming by characterizing the molecular and cognitive phenotypes associated with the pathogenic P301L tau mutation (rT2 mice) in relation to a genetically matched transgenic mouse overexpressing nonmutant (NM) 4-repeat (4R) human tau (rT1 mice). Both male and female mice were included in this study. Unexpectedly, we found that 4R NM human tau (hTau) exhibited abnormal dynamics in young mice that were lost with the P301L mutation, including elevated protein stability and hyperphosphorylation, which were associated with cognitive impairment in 5-month-old rT1 mice. Hyperphosphorylation of NM hTau was observed as early as 4 weeks of age, and transgene suppression for the first 4 or 12 weeks of life prevented abnormal molecular and cognitive phenotypes in rT1, demonstrating that NM hTau pathogenicity is specific to postnatal development. We also show that NM hTau exhibits stronger binding to microtubules than P301L hTau, and is associated with mitochondrial abnormalities. Overall, our genetically matched mice have revealed that 4R NM hTau overexpression is pathogenic in a manner distinct from classical aging-related tauopathy, underlining the importance of assaying the effects of transgenic disease-related proteins at appropriate stages in life.

Original languageEnglish (US)
Pages (from-to)220-236
Number of pages17
JournalJournal of Neuroscience
Issue number1
StatePublished - Jan 2 2020


  • Mouse model
  • Tau
  • Tauopathy
  • Transgenesis

ASJC Scopus subject areas

  • Neuroscience(all)


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