Species: Mouse
Genes: Mthfr, APOE, Trem2
Mutations: TREM2 R47H
Modification: Mthfr: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Mthfr^em1Adiuj Apoe^{tm1.1(APOE*4)Adiuj} Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 030922. Cryopreserved.

Summary

The epsilon-4 allele of Apoliporotein E 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. The C677T variant of MTHFR (methylenetetrahydrofolate reductase), which increases plasma homocysteine levels, is also associated with an increased risk of AD (Peng et al., 2015).

This triple mutant line carries a humanized Apoe gene (ε4 allele), the R47H mutation knocked into mouse Trem2, and the A262V mutation knocked into mouse Mthfr. The latter amino acid substitution models the human C677T polymorphism. This line may be useful for studying late-onset sporadic Alzheimer’s disease.

Mice that are homozygous for the humanized Apoe and Trem2 R47H knock-in alleles and heterozygous for the knock-in Mthfr allele are viable and fertile. Viability and fertility of mice homozygous for all three mutant alleles have not been tested.

Although levels of Trem2 transcripts have not been reported for Mthfr*C677T/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 A262V (GCC > GTC) mutation into the Mthfr gene of APOE4/Trem2*R47H mice—double mutant mice with a humanized APOE4 gene and the R47H point mutation knocked into the mouse Trem2 gene. 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

Research Models Citations

1. Trem2 R47H KI (JAX)
2. Trem2 R47H KI (Haass)
3. Trem2 R47H KI (Lamb/Landreth)
4. Trem2 R47H KI x APOE4 (LOAD1)

News Citations

1. Model Morass? R47H Mutation Scuttles TREM2 Expression in Mice, Not People 13 Sep 2018

Paper Citations

1. Peng Q, Lao X, Huang X, Qin X, Li S, Zeng Z. The MTHFR C677T polymorphism contributes to increased risk of Alzheimer's disease: evidence based on 40 case-control studies. Neurosci Lett. 2015 Jan 23;586:36-42. Epub 2014 Dec 5 PubMed.
2. 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.

Other Citations

1. R47H variant of TREM2

External Citations

1. The Jackson Laboratory, Stock# 030922

Further Reading

No Available Further Reading