The PS19 mouse model harbors the T34 isoform of microtubule-associated protein tau with one N-terminal insert and four microtubule binding repeats (1N4R) encoding the human P301S mutation, all driven by the mouse prion protein promoter. These mice are useful in studying neurofibrillary tangles, neurodegenerative tauopathy and Alzheimer's disease.
Virginia M Lee, University of Pennsylvania
These PS19 transgenic mice (P301S Tg mice) express the P301S mutant form of human microtubule-associated protein tau (MAPT), under the direction of the mouse prion protein promoter (Prnp). The expression of the mutant human MAPT is five-fold higher than the expression of the endogenous mouse MAPT protein. Hyperphosphorylated, insoluble mutant human MAPT protein in the brain accumulates with age causing decreased microtubule binding/density. At three months of age, transgenic mice exhibit clasping and limb retraction when lifted by the tail, which progresses to limb weakness. By ten months of age the mice exhibit a hunched back and paralysis, followed by inability to feed. Transgenic mice have a median lifespan of approximately nine months with approximately 80% dying by 12 months. Histological analysis reveals neuron degeneration in hippocampus and ventricular dilatation (brain atrophy) by eight months of age, although significant neuron degeneration in the hippocampus occurs at approximately nine months of age. Neuron loss spreads to the amygdala, neocortex and entorhinal cortex by 12 months of age. Defective translocation of endoplasmic reticulum proteins in affected neurons is observed as early as three months of age. The onset of neurofibrillay tangle formation in the neocortex, amygdala, hippocampus, brain stem and spinal cord is five months of age. Transgenic mice display neuroinflammation with microglial activation and astrogliosis. The ultrastructure of the neurofibrillay tangle-like lesions detected is similar to that found in brain lesions of human Alzheimer's disease and tauopathy patients. Degradation of synaptic function is significant by six months of age. These mice cannot be bred to homozygosity as homozygous females do not mate.
The phenotype of PS19 transgenic mice described above is based on the published information available as of 2008. In 2012-2013, publications using PS19 mice on a B6C3F1 or B6C3 genetic background report attenuated formation of tau pathology (hyperphosphorylated tau inclusions prominent by 12 months of age, significant neuronal death after 12 months of age), as well as males developing tau pathology more consistently than females. It is not determined if these phenotype differences are observed for the PS19 colony at The Jackson Laboratory. To ensure genetically stability, we periodically rederive our colony onto the hybrid B6C3F1/J genetic background (Stock No. 100010). This was last performed in August 2013.
The P301S transgene was designed with the P301S mutant human microtubule-associated protein tau (MAPT*P301S) under the direction of the mouse prion protein promoter (Prnp). This transgene was injected into fertilized B6C3F1 mouse eggs. Transgenic founder animals were bred to B6C3F1/J or B6C3F1/Crl mice to establish founder line 19 (PS19). The resulting PS19 colony was maintained as hemizygotes on the B6C3F1 background before sending to The Jackson Laboratory Repository in 2008.
|Expressed Gene||MAPT, microtubule-associated protein tau, human|
|Site of Expression|
|Allele Name||transgene insertion PS19, Virginia M Y Lee|
|Allele Type||Transgenic (Humanized sequence, Inserted expressed sequence)|
|Allele Synonym(s)||P301S tau (line PS19); PS19 Tg|
|Gene Symbol and Name||Tg(Prnp-MAPT*P301S)PS19Vle, transgene insertion PS19, Virginia M Y Lee|
|Gene Synonym(s)||P301S tau (line PS19); PS19 Tg|
|Promoter||Prnp, prion protein, mouse, laboratory|
|Expressed Gene||MAPT, microtubule-associated protein tau, human|
|Strain of Origin||(C57BL/6 x C3H)F1|
|Mutations Made By|| |
Virginia Lee, University of Pennsylvania
When maintaining a live colony, these mice can be bred as hemizygotes. These mice cannot be bred to homozygosity as homozygous females do not mate.
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