Species: Mouse
Genes: APOE, Ceacam1, Trem2
Mutations: TREM2 R47H
Modification: APOE: Knock-In; Ceacam1: Knock-Out; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Apoe^{tm1.1(APOE*4)Adiuj} Ceacam1^em#1Adiuj Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 030673. Cryopreserved.

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. Ceacam1 (Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1) is a member of the immunoglobulin superfamily, with roles in blood-brain barrier permeability (Ludewig et al., 2013) and inflammation (Gray-Owen and Blumberg, 2006). It has recently been reported that rare, deleterious variants in Ceacam1 are significantly (p = 7.47 X 10^-7) more common in patients than in controls in the Alzheimer’s Disease Sequencing Project cohort (M. Sasner, personal communication; presentation at 2018 AAIC).

This triple mutant line carries a humanized APOE4 gene, the p.R47H mutation knocked into mouse Trem2, and a knock-out allele of the Ceacam1 gene. 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 knock-out Ceacam1 allele (Ceacam1^em1Adpmc) 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 Ceacam1 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 generate a knock-out mutation of the Ceacam1 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. 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. Ludewig P, Sedlacik J, Gelderblom M, Bernreuther C, Korkusuz Y, Wagener C, Gerloff C, Fiehler J, Magnus T, Horst AK. Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke. Circ Res. 2013 Sep 27;113(8):1013-22. Epub 2013 Jun 18 PubMed.
2. Gray-Owen SD, Blumberg RS. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol. 2006 Jun;6(6):433-46. PubMed.
3. 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# 030673
3. The Jackson Labortory Stock# 028709

Further Reading

No Available Further Reading