Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice

Jonathan Gilley*, Kunie Ando, Anjan Seereeram, Teresa Rodríguez-Martín, Amy M. Pooler, Laura Sturdee, Brian H. Anderton, Jean-Pierre Brion, Diane P. Hanger, Michael P. Coleman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
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Abstract

Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer's disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process, we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine and/or threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whereas its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least 2 years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalNeurobiology of Aging
Volume39
Early online date7 Dec 2015
DOIs
Publication statusPublished - 1 Mar 2016

Keywords

  • Hyperphosphorylation
  • Knockin mouse
  • Phosphodefective
  • Phosphomimetic
  • Tau
  • Tauopathy

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