Species: Mouse
Genes: Trem2, TREM2, APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: Trem2: Knock-Out; TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6 X CBA, back-crossed for at least 4 generations to C57BL/6
Availability: TREM2 mice: available through Marco Colonna; 5XFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034848; Live

Summary

Humanized TREM2 mice were created in a two-step process: First, researchers generated transgenic mice that carry BACs containing the common variant of human TREM2, including its regulatory elements. Then these BAC transgenic mice were back-crossed to Trem2^-/- mice (Turnbull et al., 2006) to yield mice that express the common variant of human TREM2 in the absence of mouse Trem2 (CV⁺mTrem2^−/−, or CV-KO). To study the effects of human TREM2 in the context of amyloidosis, CV-KO mice were crossed with 5XFAD mice to generate 5XFAD mice that express the common variant of human TREM2 but not mouse Trem2 (CV⁺mTrem2^−/−5XFAD, or CV-KO-5XFAD). (5XFAD mice express human APP and human presenilin-1, with a total of five AD-linked mutations, and aggressively deposit plaques beginning at approximately 6 weeks of age.)

Thus far, 8.5-month-old mice have been studied (Song et al., 2018).

Three hTREM2 mRNA isoforms were detected in cortices of CV-KO and CV-KO-5XFAD mice by RT-qPCR, although isoform 3 was not very abundant. The BAC used to create these mice also contains TREML1 and TREML2 genes. The low level of TREML1 transcript in CV-KO is similar to the level in Trem2^-/- (KO) brain, regardless of 5XFAD background, suggesting that there is little basal expression of the human TREML1 gene contained in the BAC. TREML2 transcripts, absent from KO brains, are elevated in CV-KO, again regardless of 5XFAD background.

Microglia cluster around amyloid plaques in 5XFAD mice, but genetic ablation of mTrem2 reduces the number of microglia surrounding plaques (Wang et al., 2016). Replacing mTrem2 with the common variant of hTREM2 rescues this deficit: CV-KO-5XFAD mice have more plaque-associated microglia than 5XFAD mice deficient in Trem2 (KO-5XFAD), and the coverage of amyloid plaques by microglial processes in CV-KO-5XFAD exceeds that in KO-5XFAD mice.

Amyloid plaque burdens in cortex, hippocampus, and subiculum were similar in CV-KO-5XFAD and KO-5XFAD models. Consistent with the histological observations, levels of guanidine-extractable Aβ40 and Aβ42 in cortex and hippocampus were similar in the two genotypes. There was a modest decrease in PBS-soluble Aβ in hippocampus in CV-KO-5XFAD compared with KO-5XFAD mice.

The neurodegeneration-associated microglial activation markers Cst7, Spp1, and Gpnmb were elevated in CV-KO-5XFAD compared with KO-5XFAD.

CV-KO-5XFAD mice have also been compared with 5XFAD mice carrying the R47H variant of human TREM2. See TREM2, humanized (R47H variant) X 5XFAD for details.

Modification Details

BAC transgenic mice carrying human TREM2 (common variant), TREML1, and TREML2 were back-crossed to Trem2 KO mice (Colonna) to yield mice that express the common variant of human TREM2 in the absence of mouse Trem2. These mice were then crossed with 5XFAD mice.

Phenotype Characterization

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References

Research Models Citations

1. Trem2 KO (Colonna)
2. 5xFAD (C57BL6)
3. TREM2, humanized (R47H) X 5XFAD

Paper Citations

1. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, Hernandez M, Colonna M. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol. 2006 Sep 15;177(6):3520-4. PubMed.
2. Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med. 2018 Mar 5;215(3):745-760. Epub 2018 Jan 10 PubMed.
3. Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, Yuan P, Mahan TE, Shi Y, Gilfillan S, Cella M, Grutzendler J, DeMattos RB, Cirrito JR, Holtzman DM, Colonna M. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016 May 2;213(5):667-75. Epub 2016 Apr 18 PubMed.

External Citations

1. Marco Colonna
2. JAX MMRRC Stock# 034848

Further Reading