Species: Rat
Genes: Trem2, App
Mutations: TREM2 R47H
Modification: Trem2: Knock-In; App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Long-Evans
Availability: Available through Luciano D'Adamio.

Summary

R47H is a rare variant in TREM2 that triples the risk of Alzheimer’s disease in heterozygous carriers. This knock-in rat model carries the R47H mutation in the rat Trem2 gene and a humanized Aβ sequence within the rat App gene (Tambini and D’Adamio, 2020). These R47H knock-in rats exhibit normal Trem2 splicing and expression, unlike murine Trem2 R47H knock-in lines (e.g., Trem2 R47H KI (JAX), Trem2 R47H KI (Haass), Trem2 R47H KI (Lamb/Landreth)), in which the R47H mutation led to the introduction of a cryptic splice site, mis-splicing, and Trem2 haploinsufficiency. This knock-in model should be particularly useful for studies of the effects of the Trem2 R47H mutation in the context of human Aβ.

In the following description, Trem2^w/w, Trem2^R47H/w, and Trem2^R47H/R47H refer to rats homozygous for wild-type Trem2, heterozygous for the R47H mutation in Trem2, and homozygous for the R47H mutation, respectively. All animals are on a background of a humanized Aβ sequence within App.

Trem2 splicing and expression, assessed in 20-day-old animals, were normal in the brains of rats carrying the R47H mutation. Three Trem2 transcripts were generated in the brains of Trem2^w/w rats, resulting from alternative splicing of exon 5. These same three transcripts were found in Trem2^R47H/w and Trem2^R47H/R47H brains, and the levels of the transcripts were similar among the genotypes.

Trem2 mRNA levels were also measured in microglia isolated from 4-week-old rats and did not differ between Trem2^w/w, Trem2^R47H/w, and Trem2^R47H/R47H microglia.

TREM2 protein levels in brain extracts from 1.5- to 2-month-old rats, assessed by western blot, were similar among the three genotypes. Levels of sTREM2 in the brains of 4-week-old animals were also similar among the genotypes and did not vary by sex.

Levels of APP and its cleavage products were evaluated in brain extracts from 4-week-old rats. Levels of full-length APP, APP C-terminal fragments (CTFα and CTFβ), Aβ40, Aβ42, and the Aβ42/Aβ40 ratio did not vary by genotype or sex. However, levels of Aβ38 were decreased in male carriers of the R47H mutation, compared with rats homozygous for wild-type Trem2. Small decreases in sAPPα and sAPPβ were seen in homozygous carriers of the R47H mutation, compared with rats homozygous for wild-type Trem2, when sexes were pooled.

Modification Details

CRISPR/Cas9 was used to introduce the R47H mutation into the endogenous rat Trem2 gene. Trem2-mutation carriers were crossed five times to wild-type Long-Evans rats to reduce the probability of off-target mutations.

Animals carrying the Trem2 R47H mutation were then crossed with App^h rats (Tambini et al., 2019), in which App was mutated to carry a humanized Aβ sequence. The progeny of this cross were then bred to generate animals in which the Trem2 R47H mutation was on a background homozygous for the humanized App allele.

Related Strains

App^h knock‐in. This knock-in rat model carries a humanized Aβ sequence within the endogenous rat App gene.

Phenotype Characterization

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References

Mutations Citations

1. TREM2 R47H

Research Models Citations

1. Trem2 R47H KI (JAX)
2. Trem2 R47H KI (Haass)
3. Trem2 R47H KI (Lamb/Landreth)
4. App knock-in (humanized Aβ)

Paper Citations

1. Tambini MD, D'Adamio L. Trem2 Splicing and Expression are Preserved in a Human Aβ-producing, Rat Knock-in Model of Trem2-R47H Alzheimer's Risk Variant. Sci Rep. 2020 Mar 5;10(1):4122. PubMed.
2. Tambini MD, Yao W, D'Adamio L. Facilitation of glutamate, but not GABA, release in Familial Alzheimer's APP mutant Knock-in rats with increased β-cleavage of APP. Aging Cell. 2019 Dec;18(6):e13033. Epub 2019 Sep 9 PubMed.

Other Citations

1. Luciano D'Adamio

Further Reading

No Available Further Reading