Research Models

Snx1*D465N/APOE4/Trem2*R47H

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)-Apoetm1.1(APOE*4)Adiuj Snx1em1Adiuj Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: Available May, 2019 from The Jackson Laboratory, Stock# 031942

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

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
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

No data.

Neuronal Loss

No data.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 05 Dec 2018

COMMENTS / QUESTIONS

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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

Paper Citations

  1. . 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. . 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