Species: Mouse
Genes: Abca7, APOE, Trem2
Mutations: TREM2 R47H
Modification: Abca7: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Apoe^{tm1.1(APOE*4)Adiuj} Abca7^em#2Adiuj Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 030283. Cryopreserved.

Summary

The epsilon-4 allele of Apoliporotein E (APOE4) and the rare 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 p.A1527G allele of Abca7 is a common variant (minor allele frequency 0.16 in ExAc and HEX), which imparts a slightly increased risk for AD (odds ratio approximately 1.1, Kunkle et al., 2018).

This triple mutant line carries a humanized APOE4 gene, the p.R47H mutation knocked into mouse Trem2, and the p.A1527G mutation knocked into mouse Abca7. 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 Abca7 p.A1527G allele (Abca7^em2Adiuj) 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 Abca7*A1527G/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 rs3752246 SNP mutation (p.A1527G) into the Abca7 gene of double mutant mice with a humanized APOE4 gene and the R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoe^{tm1.1(APOE*4)Adiuj} Trem2e^m1Adiuj/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

COMMENTS / QUESTIONS

No Available Comments

Make a comment or submit a question

To make a comment you must login or register.

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. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Naj AC, Boland A, Vronskaya M, van der Lee SJ, Amlie-Wolf A, Bellenguez C, Frizatti A, Chouraki V, Alzheimer's Disease Genetics Consortium (ADGC), European Alzheimer's Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in Alzheimer's Disease Consortium (GERAD/PERADES), Schmidt H, Hakonarson H, Munger R, Schmidt R, Farrer LA, Van Broeckhoven C, O'Donovan MC, Destefano AL, Jones L, Haines JL, Deleuze JF, Owen MJ, Gudnason V, Mayeux RP, Escott-Price V, Psaty BM, Ruiz A, Ramirez A, Wang LS, van Duijn CM, Holmans PA, Seshadri S, Williams J, Amouyel P, Schellenberg GD, Lambert JC, Pericak-Vance MA. Meta-analysis of genetic association with diagnosed Alzheimer's disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing. bioRχiv. 2018 Apr 5
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.

External Citations

1. The Jackson Laboratory Stock# 028709
2. The Jackson Laboratory, Stock# 030283
3. The Jackson Laboratory Stock# 028709

Further Reading

No Available Further Reading