Research Models

Tau35

Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Genetic Background: C57BL/6 (75%) and 129/Ola (25%).
Availability: Unknown.

Summary

This model expresses a 35kD fragment of human tau (187-441 a.a.) fused to an HA tag and expressed from the human tau promotor. A single copy of the construct was knocked in to the Hprt locus. Expression of the Tau35 transgene was similar to wild-type tau and accounted for approximately 7 percent of total tau mRNA from the hippocampi and adjacent cortices of eight-month-old mice. This study utilized male littermates that were either hemizygous Tau35 or wild-type. These mice recapitulate several molecular and behavioral features of human tauopathy, including tau hyperphosphorylation, tangle formation, impaired cognition/behavior, and shortened lifespan (Bondulich et al., 2016).

These mice develop progressive tau pathology in the hippocampus. Abnormally phosphorylated tau was detected at two months and increased through 16 months. By eight months tau was mislocalized to the cytoplasm, endogenous murine tau was misfolded, and dystrophic neurites were observed. Tangle-like structures were observed by 14 months with multiple tau antibodies. Gliosis was not observed by 14 months.

In addition to tau pathology, there was also evidence of impaired lysosomal and autophagy-mediated protein degradation. Cell death was not assessed in the spinal cord or brain.

During Morris water maze testing, Tau35 mice preformed the same as wildtype controls at six months, but progressive deficits began at eight months, demonstrating impaired spatial learning and memory. Swim speed was comparable at all ages and Tau35 preformed the same as wild-type when the platform was visible. Non-associative short-term olfactory memory was spared at eight months.

Early motor impairments were a prominent phenotype. Abnormal limb clasping occurred in just 5 percent of animals at four months and in all animals by 18 months. Rotarod deficits were observed by four months even through grip strength was normal at this age. Hind limb grip strength failed to increase with age, as was observed in wild-type mice.

Muscle fibers in the quadriceps and latissimus muscles appeared to be degenerative/regenerative at eight months of age. The mice also developed progressive spine curvature starting around six months of age. The median lifespan was reduced to 717 days from the 788 days of wild-type mice. 

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Gliosis

No Data

  • Neuronal Loss
  • Plaques
  • Changes in LTP/LTD

Plaques

Unknown.

Tangles

Abnormally phosphorylated tau detected at two months and by eight months tau was mislocalized and misfolded and dystrophic neurites were observed. Tangle-like structures observed in the hippocampus by 14 months.

Neuronal Loss

Cell death was not formally assessed, however, overt neuronal death was not seen in the hippocampus.

Gliosis

Gliosis was not observed at 14 months.

Synaptic Loss

At 14 months synapsin1 protein levels were decreased but synaptophysin levels remained at wild-type levels.

Changes in LTP/LTD

Unknown.

Cognitive Impairment

In the Morris water maze, Tau35 had the same performance as wild-type animals at six months but developed progressive deficits by eight months. 

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References

Paper Citations

  1. . Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate. Brain. 2016 Aug;139(Pt 8):2290-306. Epub 2016 Jun 12 PubMed.

Further Reading

No Available Further Reading