Species: Mouse
Genes: Snx1, APOE, Trem2
Mutations: TREM2 R47H
Modification: Snx1: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Apoe^{tm1.1(APOE*4)Adiuj} Snx1^em1Adiuj Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 031942. 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. The SNX1 (sorting nexin 1) gene encodes a component of the retromer complex, involved in retrograde transport from the endosome to the Golgi. The common missense variant rs1802376 (D466N in human protein; D465N in mouse) has been associated with Alzheimer’s disease in multiple independent cohorts (Desikan et al., 2015; Sasner et al., poster at 2018 Society for Neuroscience meeting).

This triple-mutant line carries a humanized Apoe gene (ε4 allele), the R47H mutation knocked into mouse Trem2, and the D465N mutation knocked into mouse Snx1. 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 Snx1 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 Snx1*D465N/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 D465N (GAC>AAC) mutation in the Snx1 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

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

News Citations

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

Paper Citations

1. Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, Chasman DI, McEvoy LK, Holland D, Chen CH, Karow DS, Brewer JB, Hess CP, Williams J, Sims R, O'Donovan MC, Choi SH, Bis JC, Ikram MA, Gudnason V, DeStefano AL, van der Lee SJ, Psaty BM, van Duijn CM, Launer L, Seshadri S, Pericak-Vance MA, Mayeux R, Haines JL, Farrer LA, Hardy J, Ulstein ID, Aarsland D, Fladby T, White LR, Sando SB, Rongve A, Witoelar A, Djurovic S, Hyman BT, Snaedal J, Steinberg S, Stefansson H, Stefansson K, Schellenberg GD, Andreassen OA, Dale AM, Inflammation Working Group and International Genomics of Alzheimer’s Disease Project (IGAP) and DemGene Investigators†. Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease. Circulation. 2015 Jun 9;131(23):2061-9. Epub 2015 Apr 10 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. poster at 2018 Society for Neuroscience meeting
2. The Jackson Laboratory, Stock# 031942

Further Reading

No Available Further Reading