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Species: Mouse
Genes: APOE, Plcg2, Trem2
Mutations: TREM2 R47H
Modification: APOE: Knock-In; Plcg2: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Apoetm1.1(APOE*4)Adiuj Plcg2em2Adiuj Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 030674. Cryopreserved.


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. Plcg2 (phospholipase C, gamma 2) is highly expressed in microglia (Sims, et al., 2017), and the rare variant rs61749044 (p.M28L) was found to be associated with an increased risk for AD in the Alzheimer’s Disease Sequencing Project cohort (M. Sasner, personal communication; presentation at 2018 AAIC).

This triple mutant line carries a humanized APOE4 gene, the p.R47H mutation knocked into mouse Trem2, and the p.M28L mutation knocked into Plcg2. This line may be useful for studying late-onset sporadic Alzheimer’s disease.

Mice that are homozygous for the humanized APOE4 (Apoetm1.1(APOE*4)Adiuj) and Trem2 p.R47H (Trem2em1Adiuj) alleles and heterozygous for the Plcg2 p.M28L allele (Plcg2em2Adiuj) are viable and fertile.

Although levels of Trem2 transcripts have not been reported for Plcg2*M28L/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 p.M28L mutation (methionine to leucine at position 28) into the Plcg2 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+.


No Data

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


No data.


No data.

Neuronal Loss

No data.


No data.

Synaptic Loss

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 30 Nov 2018


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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. . Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 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.

External Citations

  1. presentation
  2. The Jackson Laboratory Stock# 028709
  3. The Jackson Laboratory, Stock# 030674
  4. The Jackson Laboratory Stock# 028709

Further Reading

No Available Further Reading