Genes: Clasp2, APOE, Trem2
Mutations: TREM2 R47H
Modification: Clasp2: Knock-In; APOE: Knock-In; Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Apoetm1.1(APOE*4)Adiuj Clasp2em1Adiuj Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: Available May, 2019 from The Jackson Laboratory, Stock# 031944
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. 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).
This triple-mutant line carries a humanized Apoe gene (ε4 allele), the R47H mutation knocked into mouse Trem2, and the L163P mutation knocked into mouse Clasp2. 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 Clasp2 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 Clasp2*L163P/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.
CRISPR/cas9 was used to generate a knock-in L163P (CTG>CCA) mutation of the Clasp2 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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
Changes in LTP/LTD
Last Updated: 05 Dec 2018
Research Models Citations
- 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.
No Available Further Reading