Research Models

TASTPM (TAS10 x TPM)

Synonyms: APPswe x PS1.M1466V, TAS/TPM

Species: Mouse
Genes: APP, PSEN1
Mutations: APP KM670/671NL (Swedish), PSEN1 M146V
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: TAS10 transgene originally injected into C57BL/6 x C3H oocytes, with some backcrossing to C57BL/6. TPM generated on pure C57BL/6 background.
Availability: Unknown

Summary

TASTPM is a double transgenic mouse model of Alzheimer’s disease carrying two mutations associated with early onset disease: the Swedish mutation in APP and the M146V mutation in PSEN1. The double transgenic is more commonly used than either of the parental lines (TAS10 and TPM). TASTPM mice develop several AD-related phenotypes, including age-related amyloid pathology and memory deficits, but they do not develop tangle pathology or appreciable neuronal loss. Phenotypes on this page refer to findings in heterozygous animals.

Like the parental line TAS10, the TASTPM double transgenic develops extensive amyloid pathology in the cerebral cortex and hippocampus. Sporadic Aβ deposits are evident as early as 3 months of age, although extracellular, fibrillar amyloid plaques are not observed until around six months, and continue to multiply with age. Plaques contain both Aβ40 and Aβ42, with the overall load of the latter being greater. The plaques frequently have multiple amyloid cores and are typically surrounded by dystrophic neurites and reactive astrocytes. Some amyloid deposits also appear in the cerebral vasculature. Aβ deposition begins earlier in TASTPM double transgenics (at about six months) than in TAS10 mice (at about 12 months), suggesting that the presence of mutant human presenilin-1 accelerates the rate of Aβ deposition (Howlett et al., 2004; Howlett et al., 2008).

Gender differences have been described in TASTPM mice. Female mice develop more rapid and severe amyloid pathology than males, with a greater Aβ load at all ages examined (i.e., 6, 8, and 10 months). This gender difference is apparent in both the number of deposits and the area occupied by plaques. Despite these differences in cerebral Aβ deposition, male and female mice exhibit similar deficits in object-recognition memory, with impairment starting at six months of age in both sexes.

Modification Details

This is a double transgenic generated by crossing TAS10 mice (an APP transgenic line expressing human APP695 with the Swedish mutation) with TPM mice (a PSEN1 transgenic expressing human PSEN1 with the M146V mutation). Both transgenes are driven by the murine Thy-1 promoter.

Related Strains

TAS10: An APP transgenic used to generate the TASTPM double mutant.

TPM: A PSEN1 transgenic used to generate the TASTPM double mutant.

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

  • Neuronal Loss
  • Tangles

No Data

  • Synaptic Loss
  • Changes in LTP/LTD

Neuronal Loss

Minimal neuronal loss up to 10 months of age. Some signs of loss in the immediate vicinity of plaques in the hippocampus (Howlett et al., 2008).

Plaques

Aβ begins to deposit at 3 months of age, with fibrillar plaques evident by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid is also observed. Plaque pathology is more severe in female mice.

Tangles

Absent.

Gliosis

Greater numbers of reactive astrocytes and microglia by 6 months of age in the hippocampus and cortex, predominantly near amyloid plaques.

Synaptic Loss

Unknown.

Changes in LTP/LTD

Unknown.

Cognitive Impairment

Age-dependent impairment in object recognition memory starting around 6 months of age for both sexes. No impairment at 3 to 4 months of age.

COMMENTS / QUESTIONS

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References

Research Models Citations

  1. TAS10 (thy1-APPswe)
  2. TPM (Thy-1 PS1.M146V)

Paper Citations

  1. . Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes. Brain Res. 2004 Aug 13;1017(1-2):130-6. PubMed.
  2. . Abeta deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer's disease. Histol Histopathol. 2008 Jan;23(1):67-76. PubMed.

Further Reading

Papers

  1. . NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice. J Neurosci. 2010 Sep 8;30(36):12128-37. PubMed.
  2. . TASTPM mice expressing amyloid precursor protein and presenilin-1 mutant transgenes are sensitive to γ-secretase modulation and amyloid-β₄₂ lowering by GSM-10h. Neurodegener Dis. 2011;8(1-2):15-24. PubMed.
  3. . Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice. Br J Pharmacol. 2009 May;157(1):130-8. PubMed.