Mutations: TREM2 R47H
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: C57BL/6J-Trem2em1Adiuj/J
Genetic Background: C57BL/6J
Availability: The Jackson Lab:Stock# 027918; Live
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. Similar to other Trem2 R47H knock-in lines (Trem2 R47H KI (Haass), Trem2 R47H KI (Lamb/Landreth)), these mice show decreased expression of Trem2 (Xiang et al., 2018). 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).
The behavioral data summarized here were collected by the MODEL-AD Consortium and 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 Trem2 R47H KI and C57BL/6J control mice, with both genotypes showing an age-dependent decline in these measures. Two- and 12-month-old Trem2 R47H KI mice also performed similarly to control mice in a Y-maze test of working memory.
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.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Cognitive Impairment
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
Changes in LTP/LTD
At 2 and 12 months of age, R47H KI mice perform similarly to wild-type mice in tests of locomotor activity, motor coordination, and working memory.
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.