Updated 9 July 2004

General Information

Transgene: Human longest brain tau isoform, wildtype 4 repeat tau isoform containing exons 2 and 3 as well as four microtubule-binding repeats (2+ 3+ 4R human tau40)

Mutation: P301L (pR5 construct) Line: pR5-182

Promoter: Neuron-specific elements of the mouse Thy.1.2 promoter

Mouse strain: B6D2F1 x B6D2F1, founder animals were intercrossed with C57BL/6 mice to establish lines.

Phenotype

Neuropathological Analysis:

Abnormal tau filament formation in P301L mice. Filaments were phosphorylated at distinct epitopes, and formation accompanied by astrocytosis and apoptosis. 

Tau filaments obtained from P301L mice have the same width as those in the human disease associated with Dutch family 1 mutation, but shorter than filaments enriched from AD brains. 

 Large numbers of pathologically enlarged axons containing neurofilament and tau-reactive spheroids.

In cortex, brain stem, and spinal cord, neurofibrillary tangles were identified by thioflavin-S fluorescent microscopy and Gallyas silver stains.

Injection of synthetic Ab42 fibrils into sensory cortex and hippocampus of 5- to 6-month-old P301L mice leads to a 5-fold increase (relative to uninjected Tg mice) in the number of neurofibrillary tangles found in amygdala (from which neurons project to injection sites), along with smaller numbers in parietal cortex. Injected wild-type mice did not show tangles.

Gallyas silver staining identified tangles containing tau phosphorylated at serine 212/threonine 214 and serine 422.

The neurofibrillary tangles were found as early as 18 days after injection and were composed of twisted filaments.

Neuronal lesions similar to FTDP-17

Behavioral:

Signs of Wallerian degeneration, neurogenic muscle atrophy,  muscle weakness.

P301L mice lacking exon 2 and 3 under the control of the mouse prion protein promoter show an advanced neurological phenotype.

Availability

Patents: none

Reference

Primary:

Gotz J, Chen F, Barmettler R, Nitsch RM. Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 2001 Jan 5;276(1):529-34. Abstract

Secondary:

Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Aβ42 fibrils. Science 293(5534):1491-5, 2001. Abstract.

Gotz J, Barmettler R, Ferrari A, Goedert M, Probst A, Nitsch RM. In vivo analysis of wild-type and FTDP-17 tau transgenic mice. Ann N Y Acad Sci 2000;920:126-33. Abstract.

Pennanen L, Welzl H, D'Adamo P, Nitsch RM, Götz J. Accelerated extinction of conditioned taste aversion in P301L tau transgenic mice. Neurobiol Dis. 2004 Apr ; 15(3):500-9. Abstract