Species: Mouse
Genes: TREM2
Modification: TREM2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: FVB/NJ
Availability: Available through X. William Yang.

Summary

Loss-of-function mutations in TREM2 cause Nasu-Hakola disease (Paloneva et al., 2002), a rare, autosomal-recessive disorder characterized by bone fractures and early onset frontotemporal dementia (Paloneva et al., 2015), and may confer increased risk for Alzheimer’s disease and other neurodegenerative disorders (Jay et al., 2017; Yeh et al., 2017). Conversely, an intergenic variant within the TREM locus that slightly increases levels of TREM2 and TREML1 proteins was associated with a nominally decreased risk of AD (Carasquillo et al., 2017).

TREM2-BAC mice were created in order to study the effects of increasing TREM2 gene dosage (Lee et al., 2018). The BAC transgene includes the human TREM2 gene with surrounding genomic regulatory elements. Key coding exons were deleted from the TREML1, TREML2, and TREML4 genes, which are also included in the BAC, to prevent expression of these genes. TREM2-BAC mice express normal levels of mouse Trem2 transcripts and proteins compared to wild-type mice.

No locomotor deficits were observed at 2 months of age. At 10 months of age, TREM2-BAC mice performed comparably to wild-type mice in a contextual fear conditioning test. LTP was also normal at 10 months.

In vitro, microglia isolated from TREM2-BAC mice displayed increased phagocytic activity, compared with microglia from wild-type or Trem2 KO mice.

Modification Details

The BAC (RP11-237K15) transgene contains the TREM2 coding region and surrounding genomic regions (>50 kb on each side) with conserved gene regulatory elements. Key coding exons were deleted from other TREM-like genes contained in the BAC, to prevent their expression. Transgenic mice were generated and maintained on the FVB/NJ background.

Related Strains

BAC-TREM2-GFP. To visualize expression patterns of transgenic TREM2, a BAC-TREM2-GFP reporter line was also generated (Lee et al., 2018). The BAC used to generate TREM2-BAC was modified to add a C-terminal GFP fusion to TREM2. TREM2-GFP was expressed in a subset of Iba1-positive microglia (approximately 6 percent of cortical and 9 percent of hippocampal microglia at 2 months of age), but was not expressed in neurons or astrocytes.

TREM2-BAC X 5xFAD. To study the effects of increased TREM2 gene dosage in the context of amyloidosis, TREM2-BAC mice were crossed with 5xFAD mice (Lee et al., 2018).  Increasing TREM2 gene dosage attenuated amyloid pathology, eliminated deficits in contextual fear conditioning, and partially normalized the transcriptome profile in 5xFAD mice.

TREM2-BAC X APPswe/PS1dE9. TREM2-BAC mice were also crossed with APPswe/PS1dE9, a second mouse model of amyloidosis (Lee et al., 2018). Compared with APPswe/PS1dE9 mice, TREM2-BAC X APPswe/PS1dE9 displayed altered plaque-associated microglial morphology and a reduction in Iba1 immunoreactivity. TREM2 overexpression also rescued deficits in contextual fear conditioning in APPswe/PS1dE9.

Phenotype Characterization

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References

Research Models Citations

1. TREM2-BAC X 5xFAD
2. 5xFAD (B6SJL)
3. APPswe/PSEN1dE9 (line 85)

Paper Citations

1. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002 Sep;71(3):656-62. Epub 2002 Jun 21 PubMed.
2. Paloneva J, Autti T, Hakola P, Haltia MJ. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL). In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2002 Jan 24 [updated 2015 Mar 12].
3. Jay TR, von Saucken VE, Landreth GE. TREM2 in Neurodegenerative Diseases. Mol Neurodegener. 2017 Aug 2;12(1):56. PubMed.
4. Yeh FL, Hansen DV, Sheng M. TREM2, Microglia, and Neurodegenerative Diseases. Trends Mol Med. 2017 Jun;23(6):512-533. Epub 2017 Apr 22 PubMed.
5. Carrasquillo MM, Allen M, Burgess JD, Wang X, Strickland SL, Aryal S, Siuda J, Kachadoorian ML, Medway C, Younkin CS, Nair A, Wang C, Chanana P, Serie D, Nguyen T, Lincoln S, Malphrus KG, Morgan K, Golde TE, Price ND, White CC, De Jager PL, Bennett DA, Asmann YW, Crook JE, Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N. A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimers Dement. 2017 Jun;13(6):663-673. Epub 2016 Dec 8 PubMed.
6. Lee CY, Daggett A, Gu X, Jiang LL, Langfelder P, Li X, Wang N, Zhao Y, Park CS, Cooper Y, Ferando I, Mody I, Coppola G, Xu H, Yang XW. Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models. Neuron. 2018 Mar 7;97(5):1032-1048.e5. PubMed.

External Citations

1. X. William Yang

Further Reading