Species: Mouse
Genes: TREM2, Trem2
Modification: TREM2: Transgenic; Trem2: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6 ×CBA, backcrossed for at least four generations to C57BL/6.
Availability: TREM2 mice are available through Marco Colonna.

Summary

This mouse model, referred to here as TREM2^CV, expresses the common variant of human TREM2 in the absence of mouse Trem2. Transgenic TREM2 is expressed in microglia and macrophages, where it was shown to function properly in an ex vivo assay. This line has been crossed with models of amyloidosis and tauopathy (see Related Strains below).

These humanized TREM2 mice were created in a two-step process: First, transgenic mice were generated that carry BACs containing the common variant of human TREM2 including its regulatory elements, TREML1, and TREML2. Then these BAC transgenic mice were backcrossed to Trem2^-/- mice (Turnbull et al., 2006). A second BAC transgenic line, expressing the R47H variant of TREM2, was created in parallel and is described elsewhere. 

The description below refers to 8.5-month-old mice (Song et al., 2018).

Three human TREM2 mRNA isoforms were detected in the cortices of TREM2^CV mice by RT-qPCR, although isoform 3 was not very abundant. The low level of TREML1 transcript in TREM2^CV brains was similar to the level in Trem2^-/- brains, suggesting that there was little basal expression of the human TREML1 gene contained in the BAC. TREML2 transcripts, absent from Trem2^-/- brains, were elevated in TREM2^CV.

It is not known whether the level of human TREM2 in TREM2^CV mice is similar to that of endogenous mouse TREM2 in wild-type animals.

In the brain, human TREM2 was localized to microglia.

Staining for the microglial marker Iba1 was similar in the brains of Trem2^-/- and TREM2^CV mice. TYRO protein tyrosine kinase-binding protein (TYROBP) is another microglial marker, which functions as an adapter protein for TREM2; levels of Tyrobp mRNA did not differ between Trem2^-/- and TREM2^CV mice.

Expression of Cst7, Spp1 and Gpnmb, which are upregulated in disease-associated microglia (Keren-Shaul et al., 2017), was low in TREM2^CV brains.

In an ex vivo assay, bone-marrow-derived macrophages isolated from TREM2^CV mice were better able to survive growth-factor withdrawal than were cells from Trem2^-/- animals, and viability of the TREM2^CV cells was further enhanced by treatment with the TREM2 ligand HDL.

Modification Details

BAC transgenic mice carrying human TREM2 (common variant), TREML1, and TREML2 were backcrossed to Trem2 knockout mice to yield mice that express the common variant of human TREM2 in the absence of mouse Trem2.

Related Strains

TREM2, humanized (common variant) X 5XFAD. To study the effects of human TREM2 in the context of amyloidosis, TREM2^CV mice were crossed with 5XFAD mice, to generate 5XFAD mice that express the common variant of human TREM2 but not mouse Trem2. (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.)

TREM2, humanized (common variant) X PS19. To study the effects of human TREM2 in the context of tauopathy, TREM2^CV mice were crossed with PS19, to generate PS19 mice that express the common variant of human TREM2 but not mouse Trem2. (PS19 mice express human tau (1N4R) with the FTD-linked P301S mutation, and exhibit substantial neurofibrillary tangles, gliosis, and brain atrophy by 9 months of age.)

Phenotype Characterization

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References

Research Models Citations

1. Trem2 KO (Colonna)
2. TREM2, humanized (R47H)
3. TREM2, humanized (common variant) X 5XFAD
4. PS19 with humanized TREM2 (common variant)

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. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

Other Citations

1. Marco Colonna

Further Reading

No Available Further Reading