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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  1. 1.

    & A century of Alzheimer's disease. Science 314, 777–781 (2006).

  2. 2.

    & Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

  3. 3.

    et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998).

  4. 4.

    et al. Association of missense and 5´-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).

  5. 5.

    et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl Acad. Sci. USA 95, 7737–7741 (1998).

  6. 6.

    et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002).

  7. 7.

    et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 99, 469–481 (2000).

  8. 8.

    , & Tauopathy models and human neuropathology: similarities and differences. Acta Neuropathol. 115, 39–53 (2008).

  9. 9.

    , , , & Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 3, 519–526 (1989).

  10. 10.

    Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morphol. Acad. Sci. Hung. 19, 1–8 (1971).

  11. 11.

    , , & Silver impregnation of Alzheimer's neurofibrillary changes counterstained for basophilic material and lipofuscin pigment. Stain Technol. 63, 197–200 (1988).

  12. 12.

    , & Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).

  13. 13.

    & Abnormal tau-containing filaments in neurodegenerative diseases. J. Struct. Biol. 130, 271–279 (2000).

  14. 14.

    Prions. Proc. Natl Acad. Sci. USA 95, 13363–13383 (1998).

  15. 15.

    et al. Synthetic mammalian prions. Science 305, 673–676 (2004).

  16. 16.

    et al. Evidence for seeding of β-amyloid by intracerebral infusion of Alzheimer brain extracts in β amyloid precursor protein-transgenic mice. J. Neurosci. 15, 3606–3611 (2000).

  17. 17.

    et al. Exogenous induction of cerebral β-amyloidosis is governed by agent and host. Science 313, 1781–1784 (2006).

  18. 18.

    , , & Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ 42 fibrils. Science 293, 1491–1495 (2001).

  19. 19.

    et al. Induction of tau pathology by intracerebral infusion of amyloid-β-containing brain extract and by amyloid-β deposition in APP X tau transgenic mice. Am. J. Pathol. 171, 2012–2020 (2007).

  20. 20.

    et al. Transmission of mouse senile amyloidosis. Lab. Invest. 81, 493–499 (2001).

  21. 21.

    et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979–6984 (2002).

  22. 22.

    , , & Inducible proteopathies. Trends Neurosci. 29, 438–443 (2006).

  23. 23.

    et al. Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-1. Neurobiol. Dis. 15, 47–60 (2004).

  24. 24.

    et al. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nature Neurosci. 9, 108–118 (2006).

  25. 25.

    , , & Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J. Neurosci. 27, 9115–9129 (2007).

  26. 26.

    et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

  27. 27.

    , , , & Research in motion: the enigma of Parkinson's disease pathology spread. Nature Rev. Neurosci. 9, 741–745 (2008).

  28. 28.

    et al. Human spongiform encephalopathy: The National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35, 513–529 (1994).

  29. 29.

    et al. Affinity purification of human tau proteins and the construction of a sensitive sandwich enzyme-linked immunosorbent assay for human tau detection. J. Neurochem. 58, 548–553 (1992).

  30. 30.

    , & Monoclonal antibody AT8 recognises tau protein phosphorylated at both serine 202 and threonine 205. Neurosci. Lett. 189, 167–170 (1995).

  31. 31.

    & Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38δ or JNK2 in the presence of heparin generates the AT100 epitope. J. Neurochem. 99, 154–164 (2006).

  32. 32.

    et al. Epitopes that span the tau molecule are shared with paired helical filaments. Neuron 1, 817–825 (1988).

  33. 33.

    Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc. Natl Acad. Sci. USA 88, 2288–2292 (1991).

  34. 34.

    , , & Tau proteins of Alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168 (1992).

  35. 35.

    & The mouse brain in stereotaxic coordinates. (Academic Press, New York, 2001).

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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.

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    • Michel Goedert
    •  & Markus Tolnay

    These authors contributed equally to this work


  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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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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