Abstract Tau is a microtubule-associated protein that promotes polymerization and stabilization of microtubules. It is the major component of fibrillary neuronal and glial inclusions in Alzheimer's disease (AD) and the tauopathies. An autosomal dominant familial tauopathy, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), has been shown to be caused by pathogenic tau mutations. Neuropathologic features of FTDP-17 are filamentous tau aggregates in neurons and glia. Previous transgenic mice carrying the normal human tau gene developed motor neuron disease and had dystrophic axons, but no neurofibrillary tangles (NFT). In this report we describe ultrastructural features of NFT in transgenic mice carrying a mutant human tau gene. The mice were generated with a tau cDNA containing exon 1, 4, 5, 7, 9, 10, 11-13, intron 13 and exon 14, driven by the mouse prion promoter (MoPrP) and containing the most common FTDP-17 mutation, P301L. The transgenic construct was generated by ligating the P301L tau cDNA with the mouse prion promoter.
Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP
JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant β-amyloid precursor protein (APP), thus modulating the APP-Aβ (β-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Aβ deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Aβ influences the formation of neurofibrillary tangles. The interaction between Aβ and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.