B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J

Stock number: 008169
Product name: Tau P301S (PS19)
Research areas: Neurobiology Research

Description

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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.

Detailed description

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 refresh our colony onto the hybrid B6C3F1/J genetic background (Stock No. 100010). This was last performed March to November 2016.

As of October 2017, the Stock No. 008169 live colony is homozygous for the C57BL/6-derived functional Pde6b⁺ allele (the C3H-derived Pde6b^rd1 allele has been selectively removed). As of May 2019, the Stock No. 008169 live colony is homozygous for the Tlr4⁺ allele.

Development

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.

As of October 2017, the Stock No. 008169 live colony is homozygous for the C57BL/6-derived functional Pde6b⁺ allele (the C3H-derived Pde6b^rd1 allele has been selectively removed). As of May 2019, the Stock No. 008169 live colony is homozygous for the Tlr4⁺ allele.

Allele

Symbol: Tg(Prnp-MAPT*P301S)PS19Vle
Name: transgene insertion PS19, Virginia M Y Lee
MGI accession ID: MGI:3768407
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: P301S tau (line PS19); PS19 Tg
Marker symbol: Tg(Prnp-MAPT*P301S)PS19Vle
Marker name: transgene insertion PS19, Virginia M Y Lee
Marker synonyms: P301S tau (line PS19); PS19 Tg
Chromosome: 3
Strain of origin: (C57BL/6 x C3H)F1
Expressed genes: MAPT,microtubule associated protein tau,human
Molecular note: The transgene construct contains the P301S mutant human microtubule-associated protein tau, MAPT, under the direction of the mouse prion protein, Prnp, promoter. The expression of the mutant human MAPT is 5-fold higher than the expression of the endogenous mouse Mapt protein. Transgene insertion occurred on Chr 3, causing a 249 Kb deletion.