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.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health National Research Service Award F31 AG057104-01, Alzheimer's Association Zenith Award 453589, and National Institutes of Health/National Institute of Neurological Disorders and Stroke R01 NS079374-02. We thank Mr. Yung Kim and Dr. Mark Sanders at the University of Minnesota University Imaging Center, where live cell imaging was conducted; Dr. Kathleen Zahs for technical assistance with the human tau ELISAs; Dr. Pascal Verdier-Pinard for advising us in the MT experiments; and Samuel Peters for his technical assistance in making neuronal cultures.
© 2020 the authors
Copyright 2020 Elsevier B.V., All rights reserved.
- Mouse model
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't