Mutations: TREM2 R47H
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL6/J
Availability: Available through Gary Landreth or Bruce Lamb.
R47H is a rare variant in TREM2 that triples the risk of Alzheimer’s disease in heterozygous carriers. To create a mouse model carrying a single copy of R47H Trem2 under the control of its natural regulatory elements, CRISPR/Cas9 was used to introduce the R47H variant into the endogenous mouse Trem2 gene (Cheng-Hathaway et al., 2018). Similar to other Trem2 R47H knock-in lines (Trem2 R47H (Haass), Trem2 R47H KI (JAX)), these mice show decreased expression of Trem2. Lower Trem2 expression in R47H knock-in mice has been traced to aberrant splicing of the mutant allele, which introduces a premature stop codon and could promote nonsense-mediated decay (Xiang et al., 2018). The R47H mutation does not, however, induce mis-splicing or reduce expression of human TREM2 (Xiang et al., 2018; for discussion on extrapolating findings from R47H knock-in mice to humans, see Sept 2018 news).
Two independent founder lines (R104 and R1019), heterozygous for the R47H variant, were established. Thus far, information is available from generations F1–F3. The two lines are phenotypically similar, lessening the chance that any phenotypes are due to unrecognized off-target effects in these early generations.
Introduction of the R47H mutation was found to decrease Trem2 transcript levels. Levels of Trem2 mRNA were 42 percent lower in cortical lysates from Trem2+/R47H mice than in lysates from Trem2+/+ mice.
No 6E10- or Thioflavin S-positive amyloid plaques were observed at four months of age.
CRISPR/Cas9 was used to introduce the R47H variant into the endogenous mouse Trem2 gene. No off-target mutations were identified by whole-genome sequencing in founder lines R104 and R1019.
APPPS1-21;Trem2+/R47H. In order to study the effects of R47H TREM2 in the context of amyloidosis, Trem2+/R47H mice were crossed with APPPS1-21 mice, which express human APP with the Swedish mutation and human PSEN1 with the L166P mutation.
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
No 6E10- or Thioflavin S-positive amyloid plaques were observed at 4 months of age.
Changes in LTP/LTD
Last Updated: 05 Aug 2018
Research Models Citations
- Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM, Puntambekar SS, von Saucken VE, Williams RY, Karlo JC, Moutinho M, Xu G, Ransohoff RM, Lamb BT, Landreth GE. The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Mol Neurodegener. 2018 Jun 1;13(1):29. 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.