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


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.

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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.


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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.).

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Correspondence to Mike Hutton.

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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).

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