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

Jada Lewis, Eileen McGowan, Julia Rockwood, 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, Peter Davies, Mike Hutton

Research output: Contribution to journalArticlepeer-review

1000 Scopus citations

Abstract

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (P5P) and corticobasal degeneration (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 neurodegeneration. Expression of human tau containing the most common 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.

Original languageEnglish (US)
Pages (from-to)402-405
Number of pages4
JournalNature Genetics
Volume25
Issue number4
DOIs
StatePublished - 2000
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L)tau protein'. Together they form a unique fingerprint.

Cite this