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Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein.

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 acid-soluble 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.

Pubmed ID: 12417659

Authors

  • Allen B
  • Ingram E
  • Takao M
  • Smith MJ
  • Jakes R
  • Virdee K
  • Yoshida H
  • Holzer M
  • Craxton M
  • Emson PC
  • Atzori C
  • Migheli A
  • Crowther RA
  • Ghetti B
  • Spillantini MG
  • Goedert M

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

November 1, 2002

Associated Grants

  • Agency: NIA NIH HHS, Id: P30 AG10133
  • Agency: NINDS NIH HHS, Id: R01 NS14426

Mesh Terms

  • Amino Acid Substitution
  • Animals
  • Apoptosis
  • Brain
  • Brain Chemistry
  • Cell Count
  • Disease Models, Animal
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Motor Neurons
  • Neurodegenerative Diseases
  • Paraparesis
  • Phenotype
  • Phosphorylation
  • Sarcosine
  • Solubility
  • Spinal Cord
  • Thiazoles
  • tau Proteins