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Abstract

Hyperphosphorylated tau makes up the filamentous intracellular inclusions of several neurodegenerative diseases, including Alzheimer's disease1. In the disease process, neuronal tau inclusions first appear in the transentorhinal cortex from where they seem to spread to the hippocampal formation and neocortex2. Cognitive impairment becomes manifest when inclusions reach the hippocampus, with abundant neocortical tau inclusions and extracellular β-amyloid deposits being the defining pathological hallmarks of Alzheimer's disease. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease, progressive supranuclear palsy, corticobasal degeneration and other diseases1. Tau mutations cause familial forms of frontotemporal dementia, establishing that tau protein dysfunction is sufficient to cause neurodegeneration and dementia3,4,5. Thus, transgenic mice expressing mutant (for example, P301S) human tau in nerve cells show the essential features of tauopathies, including neurodegeneration and abundant filaments made of hyperphosphorylated tau protein6,8. By contrast, mouse lines expressing single isoforms of wild-type human tau do not produce tau filaments or show neurodegeneration7,8. Here we have used tau-expressing lines to investigate whether experimental tauopathy can be transmitted. We show that injection of brain extract from mutant P301S tau-expressing mice into the brain of transgenic wild-type tau-expressing animals induces assembly of wild-type human tau into filaments and spreading of pathology from the site of injection to neighbouring brain regions.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (3100AO-120261) (M.T.), the Alzheimer Association (ZEN-06-27341), the German National Genome Network (NGFN-Plus) and the German Competence Network in Degenerative Dementias (01GI0705) (M.J.), the U.K. Medical Research Council (R.A.C, G.F., M.G.) and the U.K. Alzheimer's Research Trust (M.G.). We thank K.H. Wiederhold (Novartis Institutes for Biomedical Research, Basel) and N. Schaeren-Wiemers (University Hospital Basel) for antibodies and helpful discussions.

Author information

Author notes

    • Michel Goedert
    •  & Markus Tolnay

    These authors contributed equally to this work

Affiliations

  1. Department of Neuropathology, Institute of Pathology, University of Basel, Basel, Switzerland.

    • Florence Clavaguera
    • , Stephan Frank
    • , Alphonse Probst
    •  & Markus Tolnay
  2. Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

    • Tristan Bolmont
    •  & Mathias Jucker
  3. MRC Laboratory of Molecular Biology, Cambridge, UK.

    • R. Anthony Crowther
    • , Graham Fraser
    •  & Michel Goedert
  4. Novartis Institutes for Biomedical Research, Basel, Switzerland.

    • Dorothee Abramowski
    • , Martin Beibel
    •  & Matthias Staufenbiel
  5. Neurology and Neurobiology, University Hospital, Basel, Switzerland.

    • Anna K. Stalder

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Contributions

F.C., R.A.C., M.G. and M.T. designed the experiments, coordinated the project and wrote the manuscript. M.J. initiated the study. F.C., T.B., R.A.C. D.A., G.F., A.K.S. and M.G. performed the experimental work. A.P. assisted with assessment and interpretation of initiation and neuroanatomical spreading of tau pathology. M.B. performed statistical analyses. M.S., S.F. and M.J. contributed to data and manuscript discussions.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michel Goedert or Markus Tolnay.

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DOI

https://doi.org/10.1038/ncb1901

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