Research Models

App KO/APOE4/Trem2*R47H

Species: Mouse
Genes: APOE, App, Trem2
Mutations: TREM2 R47H
Modification: APOE: Knock-In; App: Knock-Out; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Apoetm1.1(APOE*4)Adiuj Appem2Adiuj Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: Available February, 2019 from The Jackson Laboratory, Stock# 031722

Summary

The epsilon-4 allele of Apoliporotein E (APOE4) and the R47H variant of TREM2 have each been found to confer an approximately threefold increased risk for Alzheimer’s disease in humans heterozygous for either allele.  This triple mutant line carries a humanized APOE4 gene, the p.R47H mutation knocked into mouse Trem2, and a 94-bp deletion in exon 14 (APP695 numbering) of the mouse App gene. This line may be useful for studying late-onset, sporadic Alzheimer's disease.

Although levels of Trem2 transcripts have not been reported for App KO/APOE4/Trem2*R47H mice, Jackson Labs has noted that Trem2 expression is decreased by approximately 50 percent in the brains of its homozygous Trem2 R47H KI  mice. Decreased Trem2 expression has also been observed in other Trem2 R47H knock-in lines (Trem2 R47H KI (Haass), Trem2 R47H KI (Lamb/Landreth)), and has been traced to aberrant splicing of the mutant mouse allele (Xiang et al., 2018). The R47H mutation does not, however, reduce expression of human TREM2 (Xiang et al., 2018). For discussion on extrapolating findings from R47H knock-in mice to humans, see Sep 2018 news.

Modification Details

CRISPR/Cas9 was used to introduce a 94-bp deletion in exon 14 (APP695 numbering) of  the App gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J, The Jackson Laboratory Stock# 028709). To humanize the mouse Apoe gene, exons 2, 3 and most of exon 4 of the mouse Apoe gene were replaced by human APOE4 gene sequence including exons 2, 3 and 4, and some 3' UTR sequence.

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

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

No data.

Neuronal Loss

No data.

Gliosis

No data.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 30 Nov 2018

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References

Mutations Citations

  1. TREM2 R47H

Research Models Citations

  1. Trem2 R47H KI (JAX)
  2. Trem2 R47H KI (Haass)
  3. Trem2 R47H KI (Lamb/Landreth)

News Citations

  1. Model Morass? R47H Mutation Scuttles TREM2 Expression in Mice, Not People

Paper Citations

  1. . The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans. Mol Neurodegener. 2018 Sep 6;13(1):49. PubMed.

External Citations

  1. The Jackson Laboratory Stock# 028709
  2. The Jackson Laboratory, Stock# 031722
  3. The Jackson Laboratory Stock# 028709

Further Reading

No Available Further Reading