Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301s tau protein

Bridget Allen, Esther Ingram, Masaki Takao, Michael J. Smith, Ross Jakes, Kanwar Virdee, Hirotaka Yoshida, Max Holzer, Molly Craxton, Piers C. Emson, Cristiana Atzori, Antonio Migheli, R. Anthony Crowther, Bernardino Ghetti, Maria Grazia Spillantini, Michel Goedert

Research output: Contribution to journalArticle

422 Scopus citations

Abstract

The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acidsoluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.

Original languageEnglish (US)
Pages (from-to)9340-9351
Number of pages12
JournalJournal of Neuroscience
Volume22
Issue number21
DOIs
StatePublished - Nov 1 2002

Keywords

  • Hyperphosphorylation
  • MAP kinase family
  • Neurodegeneration
  • Tau filaments
  • Tau gene mutations
  • Tauopathy

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301s tau protein'. Together they form a unique fingerprint.

  • Cite this

    Allen, B., Ingram, E., Takao, M., Smith, M. J., Jakes, R., Virdee, K., Yoshida, H., Holzer, M., Craxton, M., Emson, P. C., Atzori, C., Migheli, A., Anthony Crowther, R., Ghetti, B., Spillantini, M. G., & Goedert, M. (2002). Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301s tau protein. Journal of Neuroscience, 22(21), 9340-9351. https://doi.org/10.1523/jneurosci.22-21-09340.2002