Research Models

Abca7 KO/APOE4/Trem2*R47H

Species: Mouse
Genes: Abca7, APOE, Trem2
Mutations: TREM2 R47H
Modification: Abca7: Knock-Out; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Apoetm1.1(APOE*4)Adiuj Abca7em#1Adiuj Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: Available January, 2019 from The Jackson Laboratory, Stock# 030320

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. Variants in ABCA7, a member of the highly conserved superfamily of ATP-binding cassette (ABC) transporters, are also associated with risk for AD (Ma et al., 2018), and ABCA7 deficiency has been shown to exacerbate amyloid pathology in transgenic mouse models of amyloidosis (Kim et al., 2013; Sakae et al., 2016; Satoh et al., 2015).

This triple mutant line carries a humanized APOE4 gene, the p.R47H mutation knocked into mouse Trem2, and a knock-out allele of the Abca7 gene. This line may be useful for studying late-onset sporadic Alzheimer’s disease.

Mice that are homozygous for the humanized APOE (Apoetm1.1(APOE*4)Adiuj) and Trem2 p.R47H (Trem2em1Adiuj) alleles and heterozygous for the knock-out Abca7 allele (Abca7em1Adpmc) 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 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 Abca7 gene of double mutant mice with a humanized APOE4 gene and the p.R47H point mutation knocked into the mouse Trem2 gene (B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/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

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

No data.

Neuronal Loss

No data.

Gliosis

No data.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 30 Nov 2018

COMMENTS / QUESTIONS

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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

Paper Citations

  1. . Meta-Analysis of the Association between Variants in ABCA7 and Alzheimer's Disease. J Alzheimers Dis. 2018;63(4):1261-1267. PubMed.
  2. . Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer's disease. J Neurosci. 2013 Mar 6;33(10):4387-94. PubMed.
  3. . ABCA7 Deficiency Accelerates Amyloid-β Generation and Alzheimer's Neuronal Pathology. J Neurosci. 2016 Mar 30;36(13):3848-59. PubMed.
  4. . ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing. J Biol Chem. 2015 Oct 2;290(40):24152-65. Epub 2015 Aug 10 PubMed.
  5. . 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# 030320
  3. The Jackson Laboratory Stock# 028709

Further Reading

No Available Further Reading