Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein (original) (raw)

Nature Genetics volume 25, pages 402–405 (2000)Cite this article

An Erratum to this article was published on 01 September 2000

Abstract

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration1 (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration2. Expression of human tau containing the most common3,4,5 FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Dickson, D.W. Neurodegenerative diseases with cytoskeletal pathology: a biochemical classification . Ann. Neurol. 42, 541– 544 (1997).
    Article CAS Google Scholar
  2. Hutton, M. Missense and splicing mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurosci. News 2, 73– 82 (1999).
    CAS Google Scholar
  3. Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393 , 702–705 (1998).
    Article CAS Google Scholar
  4. Dumanchin, C. et al. Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum. Mol. Genet. 7, 1825–1829 (1998).
    Article CAS Google Scholar
  5. Rizzu, P. et al. High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am. J. Hum. Genet. 64, 414–421 (1999).
    Article CAS Google Scholar
  6. Borchelt, D.R. et al. A vector for expressing foreign genes in the brains and hearts of transgenic mice. Genet. Anal. 13, 159 –163 (1996).
    Article CAS Google Scholar
  7. Trojanowski, J.Q. & Lee, V.M. Transgenic models of tauopathies and synucleinopathies. Brain Pathol. 9, 733–739 (1999).
    Article CAS Google Scholar
  8. Kosik, K.S., Orecchio, L.D., Bakalis, S. & Neve, R.L. Developmentally regulated expression of specific tau sequences. Neuron 2, 1389–1397 ( 1989).
    Article CAS Google Scholar
  9. Iqbal, K., Braak, E., Braak, H., Zaidi, T. & Grundke-Iqbal, I. A silver impregnation method for labeling both Alzheimer paired helical filaments and their polypeptides separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Neurobiol. Aging 12, 357–361 (1991).
    Article CAS Google Scholar
  10. Mirra, S.S. et al. Tau pathology in a family with dementia and a P301L mutation in tau. J. Neuropathol. Exp. Neurol. 58, 335–345 (1999).
    Article CAS Google Scholar
  11. Ikonomovic, M.D. et al. The loss of GluR2(3) immunoreactivity precedes neurofibrillary tangle formation in the entorhinal cortex and hippocampus of Alzheimer brains . J. Neuropathol. Exp. Neurol. 56, 1018– 1027 (1997).
    Article CAS Google Scholar
  12. Jicha, G.A., Bowser, R., Kazam, I.G. & Davies, P. Alz-50 and MC-1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau. J. Neurosci. Res. 48, 128–132 (1997).
    Article CAS Google Scholar
  13. Jicha, G.A., Berenfeld, B. & Davies, P. Sequence requirements for formation of conformational variants of tau similar to those found in Alzheimer's disease. J. Neurosci. Res. 55, 713–723 (1999).
    Article CAS Google Scholar
  14. Spillantini, M.G., Bird, T.D. & Ghetti, B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol. 8, 387–402 (1998).
    Article CAS Google Scholar
  15. Spillantini, M.G. & Goedert, M. Tau protein pathology in neurodegenerative diseases. Trends Neurosci. 21, 428–433 (1998).
    Article CAS Google Scholar
  16. Götz, J. et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform . EMBO J. 14, 1304–1313 (1995).
    Article Google Scholar
  17. Ishihara, T. et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751–762 ( 1999).
    Article CAS Google Scholar
  18. Spittaels, K. et al. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155, 2153–2165 ( 1999).
    Article CAS Google Scholar
  19. Probst, A. et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 99, 469– 481 (2000).
    Article CAS Google Scholar
  20. Sergeant, N., Wattez, A. & Delacourte, A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J. Neurochem. 72, 1243 –1249 (1999).
    Article CAS Google Scholar
  21. Greenberg, S.G. & Davies, P. A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. Proc. Natl Acad. Sci. USA 87, 5827–5831 (1990).
    Article CAS Google Scholar
  22. Greenberg, S.G., Davies, P., Schein, J.D. & Binder, L.I. Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. J. Biol. Chem. 267, 564– 569 (1992).
    CAS PubMed Google Scholar
  23. Feany, M.B. & Dickson, D.W. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am. J. Pathol. 146, 1388–1396 (1995).
    CAS PubMed PubMed Central Google Scholar

Download references

Acknowledgements

We thank S. Munger for oocyte injections; C. Zehr, L. Skipper, A. Grover and J. Adamson for genotyping; L. Rousseau and V. Philips for brain sectioning; M. McKinney for spinal cord dissections; F. Conkle, C. Ortega and D. Forste for mouse maintenance; and D. Borchelt for the MoPrP vector. This work was supported by the NIA (RO1 and PO1 grants to M.H., D.W.D., S.-H.Y., J.H., P.D.), The Mayo Foundation, The Society for Progressive Supranuclear Palsy (to D.W.D.) and The Smith Scholar Program (to M.H.).

Author information

Authors and Affiliations

  1. Mayo Clinic Jacksonville, Jacksonville, Florida, USA
    Jada Lewis, Eileen McGowan, Heather Melrose, Parimala Nacharaju, Marjon Van Slegtenhorst, Katrina Gwinn-Hardy, M. P Murphy, Matt Baker, Xin Yu, Karen Duff, John Hardy, Anthony Corral, Wen-Lang Lin, Shu-Hui Yen, Dennis W. Dickson & Mike Hutton
  2. Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA
    Julia Rockwood & Peter Davies

Authors

  1. Jada Lewis
    You can also search for this author inPubMed Google Scholar
  2. Eileen McGowan
    You can also search for this author inPubMed Google Scholar
  3. Julia Rockwood
    You can also search for this author inPubMed Google Scholar
  4. Heather Melrose
    You can also search for this author inPubMed Google Scholar
  5. Parimala Nacharaju
    You can also search for this author inPubMed Google Scholar
  6. Marjon Van Slegtenhorst
    You can also search for this author inPubMed Google Scholar
  7. Katrina Gwinn-Hardy
    You can also search for this author inPubMed Google Scholar
  8. M. P Murphy
    You can also search for this author inPubMed Google Scholar
  9. Matt Baker
    You can also search for this author inPubMed Google Scholar
  10. Xin Yu
    You can also search for this author inPubMed Google Scholar
  11. Karen Duff
    You can also search for this author inPubMed Google Scholar
  12. John Hardy
    You can also search for this author inPubMed Google Scholar
  13. Anthony Corral
    You can also search for this author inPubMed Google Scholar
  14. Wen-Lang Lin
    You can also search for this author inPubMed Google Scholar
  15. Shu-Hui Yen
    You can also search for this author inPubMed Google Scholar
  16. Dennis W. Dickson
    You can also search for this author inPubMed Google Scholar
  17. Peter Davies
    You can also search for this author inPubMed Google Scholar
  18. Mike Hutton
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toMike Hutton.

Rights and permissions

About this article

Cite this article

Lewis, J., McGowan, E., Rockwood, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.Nat Genet 25, 402–405 (2000). https://doi.org/10.1038/78078

Download citation

This article is cited by