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

  • 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Motor deficits in P301L transgenic mice.
Figure 2: Characterization of NFT from P301L (JNPL3) mice.
Figure 3: Electron microscopy of NFT in P301L (JNPL3) mice.
Figure 4: Anterior horn and neuromuscular pathology in P301L (JNPL3) mice.
Figure 5: Age-dependent increase in insoluble tau in P301L (JNPL3) mouse brains.

References

  1. 1

    Dickson, D.W. Neurodegenerative diseases with cytoskeletal pathology: a biochemical classification . Ann. Neurol. 42, 541– 544 (1997).

  2. 2

    Hutton, M. Missense and splicing mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurosci. News 2, 73– 82 (1999).

  3. 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).

  4. 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).

  5. 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).

  6. 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).

  7. 7

    Trojanowski, J.Q. & Lee, V.M. Transgenic models of tauopathies and synucleinopathies. Brain Pathol. 9, 733–739 (1999).

  8. 8

    Kosik, K.S., Orecchio, L.D., Bakalis, S. & Neve, R.L. Developmentally regulated expression of specific tau sequences. Neuron 2, 1389–1397 ( 1989).

  9. 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).

  10. 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).

  11. 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).

  12. 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).

  13. 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).

  14. 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).

  15. 15

    Spillantini, M.G. & Goedert, M. Tau protein pathology in neurodegenerative diseases. Trends Neurosci. 21, 428–433 (1998).

  16. 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).

  17. 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).

  18. 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).

  19. 19

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

  20. 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).

  21. 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).

  22. 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).

  23. 23

    Feany, M.B. & Dickson, D.W. Widespread cytoskeletal pathology characterizes corticobasal degeneration. Am. J. Pathol. 146, 1388–1396 (1995).

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

Correspondence to Mike Hutton.

Rights and permissions

Reprints 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

Further reading