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

Neurofibrillary tangles (NFT) composed of the microtubule-associated protei n tau are prominent in Alzheimer disease (AD), Pick disease, progressive su pranuclear palsy (PSP) and corticobasal degeneration(1) (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and pa rkinsonism linked to chromosome 17 (FTDP-17). thereby proving that tau dysf unction can directly result in neurodegeneration(2). Expression of human ta u containing the most common(3-5) FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-depen dent 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 neu ronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hy pothalamus, midbrain, pens, 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 axon al spheroids, anterior horn cell toss and axonal degeneration in anterior s pinal roots. We also saw peripheral neuropathy and skeletal muscle with neu rogenic atrophy. Brain and spinal cord contained insoluble tau that co-migr ated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice e xpressing P301L mutant tau mimics features of human tauopathies and provide s a model for investigating the pathogenesis of diseases with NFT.