Genes: Cr2, CR1, CR2, APOE, Trem2
Mutations: TREM2 R47H
Modification: Cr2: Knock-Out; CR1: Knock-In; CR2: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Cr2tm1(CR2,CR1)How Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Laboratory, Stock# 031668. Cryopreserved.
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. Variations in complement receptor 1 (CR1) also 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 Laboratory 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. This line may be useful for studying late-onset sporadic Alzheimer’s disease.
Mice that are homozygous for human CR1 and CR2, humanized Apoe4, and Trem2*R47H are viable and fertile.
Although levels of Trem2 transcripts have not been reported for hCR1 KI on APOE4/Trem2 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.
CRISPR/Cas9 was used to introduce an R47H point mutation and two silent mutations (lysine AAG>AAA and alanine GCC>GCA) into the mouse Trem2 gene. The silent mutations aid in genotyping and increase gene-editing efficiency.
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.
Targeted recombination was used to insert the human CR1 and CR2 genes (and the intergenic region between the two genes) at the ATG initiation codon of the mouse CR2 gene. The CR1 gene sequence has exons 4 through 20 flanked by LoxP sites and exons 13 through 20 flanked by FRT sites. When these mutant mice are bred to mice that express Cre recombinase, resulting offspring will have exons 4 through 20 of the human CR1 gene deleted, effectively ablating the human CR1 allele. When crossed to a FLP-recombinase-expressing strain, the resulting offspring will have exons 13 through 20 of the human CR1 gene deleted in the FLP-expressing tissues, generating the short form of CR1.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
Changes in LTP/LTD
Last Updated: 04 Dec 2018
Research Models Citations
- 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.
- 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.
- 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.
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