Research Models

Trem2 R47H KI x APOE4

Synonyms: APOE4/Trem2*R47H

Species: Mouse
Genes: APOE, Trem2
Mutations: TREM2 R47H
Modification: APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J
Genetic Background: B6(SJL)
Availability: The Jackson Lab:Stock# 028709; Live

Summary

The epsilon-4 allele of Apoliporotein E and the p.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. This double-mutant line was generated by crossing APOE4 KI mice, which carry a humanized APOE4 gene, to Trem2 R47H KI mice, which have an R47H point mutation knocked into the mouse Trem2 gene.  The APOE4/Trem2*R47H line serves as a standard background for the introduction of additional genes associated with late-onset AD, in the MODEL-AD project.

Mice homozygous for both alleles are viable and fertile.

The phenotypes of these mice are being studied as part of the MODEL-AD project, and the data summarized here were reported at the 2018 AAIC meeting.  At 2 and 12 months of age, locomotor activity (distance traveled in an open field test) and motor coordination (latency to fall on rotarod test) are similar in APOE4/Trem2*R47H, APOE4 KI, Trem2 R47H KI, and C57BL/6J mice, with all genotypes showing an age-dependent decline in these measures.  Two- and 12-month-old APOE4/Trem2*R47H mice also performed similarly to APOE4 KI, Trem2 R47H KI and C57BL/6J mice in a Y-maze test of working memory.

Brain imaging was used to assess metabolism (uptake of 18F-FDG) and cerebral blood flow (64Cu-PTSM) in 8-month-old mice. Compared with wild-type C57BL/6J animals, female APOE4/Trem2*R47H mice displayed hypometabolism in nine of 27 regions examined. Males showed both hypometabolism, albeit in fewer regions than females (four of 27 regions), and hypoperfusion (13 of 27 regions).

Although levels of Trem2 transcripts have not been reported for Trem2 R47H KI x APOE4 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

This double-mutant line was generated by crossing APOE4 KI mice, which carry a humanized APOE4 gene, to Trem2 R47H KI mice, which have an R47H point mutation knocked into the mouse Trem2 gene.

Related Strains

Abca7 KO/APOE4/Trem2*R47H. 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). CRISPR/cas9 was used to generate a knock-out mutation of the Abca7 gene of APOE4/Trem2*R47H mice.

Abca7*A1527G/APOE4/Trem2*R47H . The p.A1527G allele of Abca7 is a common variant that imparts a slightly increased risk for AD (Kunkle et al., 2018). CRISPR/Cas9 was used to introduce the p.A1527G mutation into the Abca7 gene of APOE4/Trem2*R47H mice.

App KO/APOE4/Trem2*R47H. CRISPR/Cas9 was used to introduce a 94-bp deletion in exon 14 (APP695 numbering) of the App gene of APOE4/Trem2*R47H mice.

hAPP/APOE4/Trem2*R47H . CRISPR/Cas9 was used to introduce the G601R, F606Y, and R609H (APP695 numbering) point mutations into the App gene of APOE4/Trem2*R47H mice, humanizing the Aβ sequence.

Ceacam1 KO/APOE4/Trem2*R47H. Rare variants in Ceacam1, a member of the immunoglobulin superfamily with roles in blood-brain barrier permeability (Ludewig et al., 2013) and inflammation (Gray-Owen and Blumberg, 2006), have been reported to associate with AD (M. Sasner, personal communication; presentation at 2018 AAIC). CRISPR/cas9 was used to generate a knock-out mutation of the Ceacam1 gene of APOE4/Trem2*R47H mice.

Clasp2*L163P/APOE4/Trem2*R47H. CLASP2 (CLIP-associating protein 2) encodes a microtubule-binding protein that promotes microtubule stabilization. The L163P variant of CLASP2 has been associated with an increased risk of Alzheimer’s disease (Sasner et al., poster at 2018 Society for Neuroscience meeting). CRISPR/Cas9 was used to generate a knock-in L163P mutation of the Clasp2 gene of APOE4/Trem2*R47H mice.

hCR1 KI on APOE4/Trem2. Variations in complement receptor 1 (CR1) have been associated with an increased risk for AD (Almeida et al., 2018) and with effects on imaging biomarkers of AD (Zhu et al., 2017). This mutant line was generated by crossing APOE4/Trem2*R47H mice to mice in which the endogenous Cr2 gene was replaced with human CR1 and CR2 (The Jackson Lab Stock# 027713). FRT and LoxP sites inserted within the human CR1 gene allow for the generation of multiple splice forms of CR1 as well as the ability to ablate human CR1 while leaving human CR2 intact.

Il1rap KO/APOE4/Trem2*R47H.  An intronic variant in Il1rap, a component of the interleukin 1 receptor complex, has been associated with higher rates of amyloid accumulation and cognitive decline, and an increased probability of converting from MCI to AD, compared with the common variant (Ramanan et al., 2015). CRISPR/cas9 was used to generate a knock-out mutation of the Il1rap gene of APOE4/Trem2*R47H mice.

Kif21b*T82T/APOE4/Trem2*R47H. The motor protein KIF21B (Kinesin Family Member 21B) has been identified as a susceptibility locus for multiple sclerosis (The International Multiple Sclerosis Genetics Consortium, 2010), and a synonymous variant in KIF21B, T82T, was found to be associated with AD risk in the Alzheimer’s Disease Sequencing Project (Sasner et al., poster at 2018 Society for Neuroscience meeting). CRISPR/CSas9 was used to generate a knock-in T82T (ACG to ACA) mutation of the Kif21b gene of APOE4/Trem2*R47H mice.

Mthfr*C677T/APOE4/Trem2*R47H. The A262V mutation of Mthfr (methylenetetrahydrofolate reductase) models the human MTHFR C677T polymorphism, which is associated with an increased risk of AD (Peng et al., 2015). CRISPR/Cas9 was used to introduce the A262V mutation into the Mthfr gene of APOE4/Trem2*R47H mice.

Plcg2*M28L/APOE4/Trem2*R47H. The p.M28L variant of Plcg2 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). CRISPR/Cas9 was used to introduce the p.M28L mutation into the Plcg2 gene of APOE4/Trem2*R47H mice.

Snx1*D465N/APOE4/Trem2*R47H. The SNX1 (sorting nexin 1) gene encodes a component of the retromer complex. 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). CRISPR/Cas9 was used to generate a D465N mutation in the Snx1 gene of APOE4/Trem2*R47H mice.

Sorl1*A528T/APOE4/Trem2*R47H. A528T is a common variant of SORL1 that increases Aβ42 secretion (Vardarajan et al., 2016) and has been shown to segregate with late-onset AD in > 50 families (Vardarajan et al., 2016) and to associate with increased risk of developing dementia in Parkinson’s disease patients (Maple-Grødem  et al., 2018). CRISPR/Cas9 was used to generate a knock-in A528T mutation of the Sorl1 gene of APOE4/Trem2*R47H mice.

 

 

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

  • Cognitive Impairment

No Data

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

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

At 2 and 12 months of age, APOE4/Trem2*R47H mice perform similarly to wild-type mice in tests of locomotor activity, motor coordination, and working memory.

Last Updated: 22 Oct 2019

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References

Research Models Citations

  1. APOE4 Knock-In (JAX)
  2. Trem2 R47H KI (JAX)
  3. Trem2 R47H KI (Haass)
  4. Trem2 R47H KI (Lamb/Landreth)
  5. Abca7 KO/APOE4/Trem2*R47H
  6. Abca7*A1527G/APOE4/Trem2*R47H
  7. App KO/APOE4/Trem2*R47H
  8. hAPP/APOE4/Trem2*R47H
  9. Ceacam1 KO/APOE4/Trem2*R47H
  10. Clasp2*L163P/APOE4/Trem2*R47H
  11. hCR1 KI on APOE4/Trem2
  12. Il1rap KO/APOE4/Trem2*R47H
  13. Kif21b*T82T/APOE4/Trem2*R47H
  14. Mthfr*C677T/APOE4/Trem2*R47H
  15. Plcg2*M28L/APOE4/Trem2*R47H
  16. Snx1*D465N/APOE4/Trem2*R47H
  17. Sorl1*A528T/APOE4/Trem2*R47H

News Citations

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

Paper Citations

  1. . 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.
  2. . Meta-Analysis of the Association between Variants in ABCA7 and Alzheimer's Disease. J Alzheimers Dis. 2018;63(4):1261-1267. PubMed.
  3. . 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
  4. . Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits MMP-9-mediated blood-brain-barrier breakdown in a mouse model for ischemic stroke. Circ Res. 2013 Sep 27;113(8):1013-22. Epub 2013 Jun 18 PubMed.
  5. . CEACAM1: contact-dependent control of immunity. Nat Rev Immunol. 2006 Jun;6(6):433-46. PubMed.
  6. . Updated Meta-Analysis of BIN1, CR1, MS4A6A, CLU, and ABCA7 Variants in Alzheimer's Disease. J Mol Neurosci. 2018 Mar;64(3):471-477. Epub 2018 Mar 4 PubMed.
  7. . Effect of CR1 Genetic Variants on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts. Mol Neurobiol. 2016 Jan 7; PubMed.
  8. . GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP. Brain. 2015 Oct;138(Pt 10):3076-88. Epub 2015 Aug 11 PubMed.
  9. . Comprehensive follow-up of the first genome-wide association study of multiple sclerosis identifies KIF21B and TMEM39A as susceptibility loci. Hum Mol Genet. 2010 Mar 1;19(5):953-62. Epub 2009 Dec 9 PubMed.
  10. . The MTHFR C677T polymorphism contributes to increased risk of Alzheimer's disease: evidence based on 40 case-control studies. Neurosci Lett. 2015 Jan 23;586:36-42. Epub 2014 Dec 5 PubMed.
  11. . Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease. Circulation. 2015 Jun 9;131(23):2061-9. Epub 2015 Apr 10 PubMed.
  12. . Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. PubMed.
  13. . Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease. Neurosci Lett. 2018 May 1;674:123-126. Epub 2018 Mar 19 PubMed.

External Citations

  1. MODEL-AD
  2. poster at 2018 Society for Neuroscience meeting
  3. The Jackson Lab Stock# 027713
  4. The Jackson Lab:Stock# 028709

Further Reading

No Available Further Reading