Species: Mouse
Genes: APOE, Trem2
Mutations: TREM2 R47H, APOE C130R (ApoE4)
Modification: APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Apoe^{tm1.1(APOE*4)Adiuj} Trem2^em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Lab:Stock# 028709; Live

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. 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 missense mutation knocked into the mouse Trem2 gene. The APOE4/Trem2*R47H line serves as a standard background, or “platform strain,” for the introduction of additional alleles associated with late-onset AD in the MODEL-AD project.

One caveat regarding this model: TREM2 protein levels in the brains of mice homozygous for the Trem2 R47H allele are approximately half those of homozygous carriers of the wild-type allele (Kotredes et al., 2021), an effect not seen in human carriers of the variant (Xiang et al., 2018). Decreased Trem2 expression has been observed in other early 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). Subsequently, Trem2*R47H knock-in lines have been created that avoid the problem of aberrant splicing and generate normal levels of Trem2 transcripts (see Trem2*R47H^HSS, Trem2*R47H^NSS).

The following description refers to APOE4/Trem2*R47H mice homozygous for both the APOE4 and Trem2 R47H alleles. (It should be noted that the vast majority of human R47H carriers reported in the literature are heterozygotes.)

Survival. APOE4/Trem2*R47H are viable and fertile. However, fewer of these mice survived to old age, compared with mice carrying the wild-type alleles: The mortality rate for wild-type C57BL/6J animals was less than 5 percent at 24 months, but approximately 20 percent for male and 35 percent for female APOE4/Trem2*R47H mice (Kotredes et al., 2021).

Behavior. Mice through 24 months of age were characterized using a battery of tests (Kotredes et al., 2021). Locomotor activity (distance traveled in an open field test, home-cage wheel running), motor coordination (latency to fall on the rotarod test), and working memory (spontaneous alternation in the Y-maze) showed normal age-related changes but no genotype-dependent differences, compared with wild-type mice.

Neuropathology. No neuron loss, amyloid plaques, neurofibrillary tangles, vascular leakage, myelin loss, or reactive microglia were observed in mice up to 24 months of age (Kotredes et al., 2021).

Brain imaging. Positron emission tomography was used to assess metabolism (uptake of ¹⁸F-FDG) and cerebral blood flow (⁶⁴Cu-PTSM) in living mice up to 24 months of age, and findings were confirmed by postmortem autoradiography (Kotredes et al., 2021). Age-, sex-, and region-dependent differences in glucose uptake were found when APOE4/Trem2*R47H mice were compared with wild-type animals. Both hypo- and hypermetabolic regions were observed. Females showed more affected areas and greater magnitudes of change than males. Age-, sex-, and region-dependent decreases in cerebral blood flow were seen in APOE4/Trem2*R47H brains through 12 months of age, compared with wild-type mice. Perfusion increased between 4 and 24 months of age in some brain regions of APOE4/Trem2*R47H animals.

Transcriptomics. There were pronounced differences between the transcriptomes of APOE4/Trem2*R47H and wild-type mice after one year of age, with the majority of differentially expressed genes being downregulated (Kotredes et al., 2021). KEGG analysis showed that downregulated genes were enriched in pathways related to immune function (‘‘antigen processing and presentation,’’ “cytokine-cytokine receptor interaction,” and ‘‘complement and coagulation cascades’’) and degradation of biological material (‘‘lysosome’’ and ‘‘phagosome’’).

Other. Compared with wild-type mice, differential splicing of neuronal genes was found in the brains of mice homozygous for the Trem2 R47H allele on a murine Apoe background (i.e., Trem2 R47H knock-in mice) and to a lesser extent in APOE4/Trem2*R47H brains (Pandey et al., 2023).

The effect of voluntary exercise was tested in aged animals. Male mice 22 to 24 months of age were provided with running wheels in their home cages. Expression of genes related to oxidative phosphorylation was upregulated in the brains of APOE4/Trem2*R47H mice given the opportunity to exercise, compared with sedentary APOE4/Trem2*R47H or wild-type animals (Kotredes et al., 2021).

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 missense 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.

hAbeta/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 has been shown to associate with a slightly increased risk of AD (~15 percent) in people of European ancestry and to segregate with disease in some families. CRISPR/Cas9 was used to generate a knock-in A528T mutation of the Sorl1 gene of APOE4/Trem2*R47H mice.

Phenotype Characterization

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. TREM2 R47H
3. SORL1 A528T (SNP 13)

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. Trem2*R47H(HSS)
6. Trem2*R47H(NSS)
7. Abca7 KO/APOE4/Trem2*R47H
8. Abca7*A1527G/APOE4/Trem2*R47H
9. App KO/APOE4/Trem2*R47H
10. Ceacam1 KO/APOE4/Trem2*R47H
11. Clasp2*L163P/APOE4/Trem2*R47H
12. hCR1 KI on APOE4/Trem2
13. Il1rap KO/APOE4/Trem2*R47H
14. Kif21b*T82T/APOE4/Trem2*R47H
15. Mthfr*C677T/APOE4/Trem2*R47H
16. Plcg2*M28L/APOE4/Trem2*R47H
17. Snx1*D465N/APOE4/Trem2*R47H
18. Sorl1*A528T/APOE4/Trem2*R47H

Paper Citations

1. Kotredes KP, Oblak A, Pandey RS, Lin PB, Garceau D, Williams H, Uyar A, O'Rourke R, O'Rourke S, Ingraham C, Bednarycek D, Belanger M, Cope Z, Foley KE, Logsdon BA, Mangravite LM, Sukoff Rizzo SJ, Territo PR, Carter GW, Sasner M, Lamb BT, Howell GR. Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H. Front Aging Neurosci. 2021;13:735524. Epub 2021 Oct 11 PubMed. Correction.
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.
3. Pandey RS, Kotredes KP, Sasner M, Howell GR, Carter GW. Differential splicing of neuronal genes in a Trem2*R47H mouse model mimics alterations associated with Alzheimer's disease. BMC Genomics. 2023 Apr 4;24(1):172. PubMed.
4. Ma FC, Wang HF, Cao XP, Tan CC, Tan L, Yu JT. Meta-Analysis of the Association between Variants in ABCA7 and Alzheimer's Disease. J Alzheimers Dis. 2018;63(4):1261-1267. PubMed.
5. 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
6. Ludewig P, Sedlacik J, Gelderblom M, Bernreuther C, Korkusuz Y, Wagener C, Gerloff C, Fiehler J, Magnus T, Horst AK. 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.
7. Gray-Owen SD, Blumberg RS. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol. 2006 Jun;6(6):433-46. PubMed.
8. Almeida JF, Dos Santos LR, Trancozo M, de Paula F. 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.
9. Zhu XC, Wang HF, Jiang T, Lu H, Tan MS, Tan CC, Tan L, Tan L, Yu JT, Alzheimer’s Disease Neuroimaging Initiative. 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.
10. Ramanan VK, Risacher SL, Nho K, Kim S, Shen L, McDonald BC, Yoder KK, Hutchins GD, West JD, Tallman EF, Gao S, Foroud TM, Farlow MR, De Jager PL, Bennett DA, Aisen PS, Petersen RC, Jack CR Jr, Toga AW, Green RC, Jagust WJ, Weiner MW, Saykin AJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI). 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.
11. International Multiple Sclerosis Genetics Consortium (IMSGC). 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.
12. Peng Q, Lao X, Huang X, Qin X, Li S, Zeng Z. 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.
13. Desikan RS, Schork AJ, Wang Y, Thompson WK, Dehghan A, Ridker PM, Chasman DI, McEvoy LK, Holland D, Chen CH, Karow DS, Brewer JB, Hess CP, Williams J, Sims R, O'Donovan MC, Choi SH, Bis JC, Ikram MA, Gudnason V, DeStefano AL, van der Lee SJ, Psaty BM, van Duijn CM, Launer L, Seshadri S, Pericak-Vance MA, Mayeux R, Haines JL, Farrer LA, Hardy J, Ulstein ID, Aarsland D, Fladby T, White LR, Sando SB, Rongve A, Witoelar A, Djurovic S, Hyman BT, Snaedal J, Steinberg S, Stefansson H, Stefansson K, Schellenberg GD, Andreassen OA, Dale AM, Inflammation Working Group and International Genomics of Alzheimer’s Disease Project (IGAP) and DemGene Investigators†. Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease. Circulation. 2015 Jun 9;131(23):2061-9. Epub 2015 Apr 10 PubMed.

Other Citations

1. hAbeta/APOE4/Trem2*R47H

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