Research Models

htau

Synonyms: human tau

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Species: Mouse
Genes: MAPT, MAPT
Modification: MAPT: Knock-Out; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia
Strain Name: B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J
Genetic Background: The targeted allele was created in 129S4/SvJae-derived J1 embryonic stem cells that were subsequently injected into C57BL/6 blastocysts. The transgenic allele was generated in embryos derived from a cross between Swiss Webster and B6D2F1. Mice containing both alleles were back-crossed to C57BL/6 mice .
Availability: The Jackson Lab: Stock# 005491; Live. Scantox Neuro offers research services with this line.

Summary

This mouse was designed to express only human tau isoforms (Andorfer et al., 2003). It was made by mating two existing lines of tau mice, 8c (Duff et al., 2000) and tau knock-out mice (Tucker et al., 2001). The 8c mice express a tau transgene via a PAC cloning vector driven by the tau promoter and produce all human tau isoforms, including 3R and 4R isoforms. Tau knockout mice were generated by targeted disruption, in which cDNA for enhanced green fluorescent protein (EGFP) was inserted into exon one of MAPT. Htau mice express six isoforms of human tau, but do not express mouse tau. Unlike the double mutant, neither 8c mice nor tau knockout mice develop tau pathology in the CNS.

Neuropathology

These mice develop age-associated tau pathology, including redistribution of tau to cell bodies and dendrites, phosphorylated tau, accumulation of aggregated paired helical filaments, and ultimately thioflavin-S-positive neurofibrillary tangles at nine to 15 months. Tau pathology is most severe in the neocortex and hippocampus, and minimal in the brain stem and spinal cord. Some regional neuronal loss was also observed (Andorfer et al., 2003; Andorfer et al., 2005).

Cognition/Behavior

Mice had normal object-recognition memory and spatial learning/memory as assessed by the Morris Water Maze at four months, but were impaired at 12 months (Polydoro et al., 2009). Abnormal spatial learning was noted in six-month-old mice compared with control mice (Phillips et al., 2011). These mice showed deficits in food burrowing at four, six, and nine months relative to control wild-type mice, but not at two or 12 months. Htau mice performed better than control mice during contextual fear extinction at nine and 12 months, but not at earlier ages. Performance on other tests (e.g., spontaneous alteration, open field, novel object, and contextual fear acquisition and memory) was largely comparable to control mice (Geiszler et al., 2016).

Other Phenotypes

General health, weight, basic reflexes, sensory responses, locomotor function, anxiety level, and gross motor function were not different from age-matched controls (Polydoro et al., 2009).

Modification Details

Double mutant mice were generated by mating mice that express human tau (8c mice) (Duff et al., 2000), with tau knockout mice that have a targeted disruption of exon 1 of tau (Tucker et al., 2001), then back-crossed to obtain mice that are homozygous for disrupted murine MAPT while carrying the human tau transgene. The human tau transgene inserted at Chr7:10447768 (Build GRCm38/mm10), where it does not affect any known genes (Goodwin et al., 2017).

Availability

The Jackson Lab: Stock# 005491; Live. The contract research organization Scantox Neuro offers research services with this line.

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

No Data

  • Gliosis
  • Synaptic Loss

Tangles

Aggregated tau and paired helical filaments detectable at nine months by immunoelectron microscopy, although paired helical filaments of aggregated insoluble tau can be isolated from brain tissue as early as two months. Tau first redistributes from axons to cell bodies. Hyperphosphorylated tau begins to accumulate by six months, and increases further by 13 and 15 months (Andorfer et al., 2003).

Neuronal Loss

Decrease in cortical thickness and reduced cell number between 10 and 14 months of age. Increased ventricle size increased from age eight months to 18 months. Decrease in the thickness of the corpus callosum (Andorfer et al., 2005).

Gliosis

Unknown.

Synaptic Loss

Unknown.

Changes in LTP/LTD

In hippocampal slices, LTP induced by high frequency stimulation (HFS) was normal at four months but abolished by 12 months. LTP induced by theta burst stimulation (TBS) was normal at both ages. Paired-pulse ratio (PPR) was unaffected at four months, but increased at 12 months compared with controls, suggesting a decrease in probability of transmitter release (Polydoro et al., 2009).

Cognitive Impairment

Abnormal spatial learning in six-month-old mice compared with control mice (Phillips et al., 2011). Normal object recognition and spatial learning and memory by MWM at four months, but deficits by 12 months (Polydoro et al., 2009). Impaired burrowing relative to control mice occurs by four months (Geiszler et al., 2016).

Last Updated: 13 Apr 2018

COMMENTS / QUESTIONS

  1. This could be the best model for studying AD like tauopathies, as these mice develop tangles without mutations. The finding that this only occurs when mouse tau is KO'ed is very interesting....

    View all comments by Todd E. Golde

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References

Paper Citations

  1. Andorfer C, Kress Y, Espinoza M, de Silva R, Tucker KL, Barde YA, Duff K, Davies P. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem. 2003 Aug;86(3):582-90. PubMed.
  2. Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M, Burki K, Davies P. Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis. 2000 Apr;7(2):87-98. PubMed.
  3. Tucker KL, Meyer M, Barde YA. Neurotrophins are required for nerve growth during development. Nat Neurosci. 2001 Jan;4(1):29-37. PubMed.
  4. Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. PubMed.
  5. Polydoro M, Acker CM, Duff K, Castillo PE, Davies P. Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology. J Neurosci. 2009 Aug 26;29(34):10741-9. PubMed.
  6. Phillips M, Boman E, Osterman H, Willhite D, Laska M. Olfactory and visuospatial learning and memory performance in two strains of Alzheimer's disease model mice--a longitudinal study. PLoS One. 2011;6(5):e19567. PubMed.
  7. Geiszler PC, Barron MR, Pardon MC. Impaired burrowing is the most prominent behavioral deficit of aging htau mice. Neuroscience. 2016 Aug 4;329:98-111. Epub 2016 May 7 PubMed.
  8. Goodwin LO, Splinter E, Davis TL, Urban R, He H, Braun RE, Chesler EJ, Kumar V, van Min M, Ndukum J, Philip VM, Reinholdt LG, Svenson K, White JK, Sasner M, Lutz C, Murray SA. Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis. bioRĪ‡iv preprint first posted online Dec. 18, 2017

External Citations

  1. The Jackson Lab: Stock# 005491
  2. Scantox Neuro
  3. The Jackson Lab: Stock# 005491
  4. Scantox Neuro

Further Reading

Papers

  1. Phillips M, Boman E, Osterman H, Willhite D, Laska M. Olfactory and visuospatial learning and memory performance in two strains of Alzheimer's disease model mice--a longitudinal study. PLoS One. 2011;6(5):e19567. PubMed.
  2. Schoch KM, DeVos SL, Miller RL, Chun SJ, Norrbom M, Wozniak DF, Dawson HN, Bennett CF, Rigo F, Miller TM. Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model. Neuron. 2016 Jun 1;90(5):941-7. Epub 2016 May 19 PubMed.