Species: Mouse
Genes: TREM2, Trem2
Mutations: TREM2 R47H
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

People who carry one copy of the R47H variant of TREM2 have an approximately threefold greater risk of developing Alzheimer’s disease than do people homozygous for the common variant. This mouse model, referred to here as TREM2^R47H, expresses the R47H variant of human TREM2 in the absence of mouse Trem2. 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 R47H 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, TREM2^CV, was created in parallel. TREM2^CV mice express the common variant of human TREM2 on a mouse-Trem2-null background and are useful controls when studying the effects of disease-associated mutations.

The description below refers to 8.5-month-old mice.

Transgene copy numbers are six to eight times greater in TREM2^CV than in TREM2^R47H mice, but TREM2 mRNA levels only differ by approximately 20 percent, and levels of TREM2 protein in hippocampus are similar in the two genotypes. Three human TREM2 mRNA isoforms were detected in cortex by RT-qPCR in animals expressing the common variant, while only two isoforms were found in mice expressing the R47H variant. TREM2^R47H brains have slightly lower levels of isoforms 1 and 2 than do TREM2^CV brains. Isoform 3 was found only in TREM2^CV brains. It is not known whether the levels of human TREM2 in TREM2^R47H or TREM2^CV mice are similar to those of endogenous mouse TREM2 in wild-type animals.

The BAC used to create these mice also contains TREML1 and TREML2 genes. The low levels of TREML1 transcript in TREM2^R47H and TREM2^CV are similar to levels in Trem2^-/- brain, suggesting that there is little basal expression of the human TREML1 gene contained in the BAC. TREML2 transcripts, absent from Trem2^-/- brains, are similarly elevated in both TREM2^R47H and TREM2^CV.

Human TREM2 was localized to microglia in the brains of TREM2^R47H and TREM2^CV mice, and levels of the protein were similar in the two genotypes.

Staining for the microglial marker Iba1 was similar in the brains of TREM2^R47H, TREM2^CV, and Trem2^-/- 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 the three genotypes.

Expression of Cst7, Spp1 and Gpnmb, which are upregulated in disease-associated microglia (Keren-Shaul et al., 2017), was low in TREM2^R47H brains.

An ex vivo assay was used to assess the function of TREM2 in bone-marrow derived macrophages isolated from these mice. Treatment with the TREM2 ligand HDL improved the viability of TREM2^R47H cells challenged with growth-factor withdrawal. The response was even greater in cells isolated from TREM2^CV mice and was absent from cells isolated from Trem2^-/- animals.

Modification Details

BAC transgenic mice carrying human TREM2 (R47H variant), TREML1, and TREML2 were backcrossed to Trem2 knockout mice to yield mice that express the R47H variant of human TREM2 in the absence of mouse Trem2.

Related Strains

TREM2, humanized (R47H variant) X 5XFAD. To study the effects of the TREM2 R47H mutation in the context of amyloidosis, TREM2^R47H mice were crossed with 5XFAD mice to generate 5XFAD mice that express the R47H 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 (R47H variant) X PS19. To study the effects of the TREM2 R47H mutation in the context of tauopathy, TREM2^R47H mice were crossed with PS19 to generate PS19 mice that express the R47H 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 (common variant)
3. TREM2, humanized (common variant) X 5XFAD
4. PS19 with humanized TREM2 (R47H)

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. 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