Species: Mouse
Genes: Sorl1, APOE, Trem2
Mutations: TREM2 R47H, SORL1 A528T (SNP 13), APOE C130R (ApoE4)
Modification: Sorl1: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Apoe^{tm1.1(APOE*4)Adiuj} Sorl1^em1Adiuj Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 031940. Cryopreserved.

Summary

The epsilon-4 allele of Apolipoprotein 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. A528T is a common variant of SORL1 that has been shown to associate with a slightly increased risk of AD (~15 percent) in people of European ancestry and to segregate with disease in some families.

This triple-mutant line carries a humanized Apoe gene (ε4 allele), the R47H mutation knocked into mouse Trem2, and the A528T mutation knocked into mouse Sorl1. 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 Sorl1 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 Sorl1*A528T/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-in A528T (GCC>ACC) mutation of the Sorl1 gene of APOE4/Trem2*R47H mice—double-mutant mice with a humanized Apoe (ε4 allele) 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

Mutations Citations

1. APOE C130R (ApoE4)
2. SORL1 A528T (SNP 13)

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. 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

External Citations

1. The Jackson Laboratory, Stock# 031940

Further Reading

No Available Further Reading