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The Journal of Neuroscience, November 1, 2002, 22(21):9340-9351
Abundant Tau Filaments and Nonapoptotic Neurodegeneration in Transgenic Mice Expressing Human P301S Tau Protein
Bridget Allen1, *, Esther Ingram2, *, Masaki Takao3, *, Michael J. Smith1, Ross Jakes1, Kanwar Virdee1, Hirotaka Yoshida1, Max Holzer1, Molly Craxton1, Piers C. Emson4, Cristiana Atzori5, Antonio Migheli5, R. Anthony Crowther1, Bernardino Ghetti3, Maria Grazia Spillantini2, and Michel Goedert1 1 Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom, 2 Brain Repair Centre and Department of Neurology, University of Cambridge, Cambridge CB2 2PY, United Kingdom, 3 Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, Indiana 46202-5120, 4 Department of Neurobiology, Babraham Institute, Cambridge CB2 4AT, United Kingdom, and 5 Laboratory of Neuropathology, Department of Neuroscience, University of Turin, 10126 Turin, Italy
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.
Key words: hyperphosphorylation; MAP kinase family; neurodegeneration; tauopathy; tau filaments; Tau gene mutations
* B.A., E.I., and M.T. contributed equally to this work.
Copyright © 2002 Society for Neuroscience 0270-6474/02/22219340-12$05.00/0
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