Species: Mouse
Genes: APOE, APP, Trem2
Mutations: TREM2 R47H
Modification: APOE: Knock-In; APP: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Apoe^{tm1.1(APOE*4)Adiuj} App^em#1Adiuj Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 030670. Live.

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 humanized Aβ sequence within the mouse App gene (the human Aβ generated by these mice is expected to be more aggregation-prone than the endogenous mouse Aβ). This line may be useful for studying late-onset sporadic Alzheimer’s disease.

Mice that are homozygous for the humanized APOE4 (Apoe^{tm1.1(APOE*4)Adiuj}) and Trem2 p.R47H (Trem2^em1Adiuj) alleles and heterozygous for the modified App allele (App^em1Adiuj) are viable and fertile. Viability and fertility of mice homozygous for all three mutant alleles has not been tested.

Although levels of Trem2 transcripts have not been reported for hAbeta/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 the G601R, F606Y, and R609H (APP₆₉₅ numbering) point mutations into 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)-Apoe^{tm1.1(APOE*4)Adiuj} Trem2^em1Adiuj/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

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. 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 13 Sep 2018

Paper Citations

1. Xiang X, Piers TM, Wefers B, Zhu K, Mallach A, Brunner B, Kleinberger G, Song W, Colonna M, Herms J, Wurst W, Pocock JM, Haass C. 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# 030670
3. Jackson Lab Stock# 028709

Further Reading

No Available Further Reading