Species: Mouse
Genes: TREM2, APP, PSEN1
Mutations: APP K670_M671delinsNL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V
Modification: TREM2: Transgenic; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: TREM2-BAC: FVB/NJ; 5xFAD: C57BL/6 X SJL
Availability: TREM2-BAC: Available through X. William Yang. 5xFAD: The Jackson Lab; available through the JAX MMRRC Stock# 034840; Live

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).

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). TREM2-BAC mice carry a transgene that includes human TREM2 with surrounding genomic regulatory elements. 5xFAD mice express human APP and human presenilin-1, with a total of five AD-linked mutations, and aggressively deposit amyloid plaques, starting at 6 weeks of age. Increasing TREM2 gene dosage attenuated amyloid pathology, eliminated deficits in contextual fear conditioning, and partially normalized the transcriptome in 5xFAD mice.

Neuropathology

The number of plaque-associated microglia was reduced in TREM2-BAC X 5xFAD (5xFAD/TREM2) mice compared with 5xFAD mice at 7 months of age. Microglial morphology also differed between genotypes: While plaque-associated microglia in 5xFAD cortex have an amoeboid shape, microglia in 5xFAD/TREM2 cortex have more elongated, ramified processes. Immunostaining for two markers associated with phagocytosis, CD68 and Lgals3, was enhanced in plaque-associated microglia in 5xFAD/TREM2, compared with 5xFAD.

Cortical amyloid plaque burden was reduced in 5xFAD/TREM2 mice compared with 5xFAD mice at 7 months of age. There was also a shift in plaque morphology from “filamentous” plaques (Aβ-immunoreactive plaques with filamentous or absent Thioflavin S staining) toward plaques with a Thioflavin S-positive core with little surrounding Aβ immunoreactivity. Concomitantly, the number of plaque-associated dystrophic neurites was reduced in 5xFAD/TREM2 mice compared with 5xFAD mice.

Transcriptome

Transcriptomic profiling identified genes that are differentially expressed in 5xFAD/TREM2 mice compared with 5xFAD mice at 4 and/or 7 months of age. Increasing TREM2 gene dosage partially normalized transcript levels for multiple damage-associated microglial genes (e.g., Cst7, Ctsd, Ctse, CtssCcl3, Ccl6, Csf1r, Abi3, and Trem2 - genes that are upregulated in 5xFAD compared with wild-type mice) and neuronal genes (e.g., Atp2b2, Grik2, Grin1, and Mapt - genes that are downregulated in 5xFAD compared with wild-type). Expression of another set of genes, upregulated in 5xFAD compared with wild-type mice, was further augmented in 5xFAD/TREM2 mice; among these are Lgals3, which promotes phagocytosis by microglia, and Spp1, which regulates cytokine expression and promotes microglia survival.

Cognition/behavior

5xFAD/TREM2 mice perform comparably to wild-type mice in a contextual fear conditioning test, while 5xFAD mice are impaired.

Modification Details

TREM2-BAC. 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.

5xFAD. 5xFAD mice express two transgenes: human APP₆₉₅ (with Swedish (K670N/M671L), Florida (I716V), and London (V717I) mutations) and human PSEN1 (with M146L and L286V mutations), each driven by the mouse Thy1 promoter.

Related Strain

TREM2-BAC X APPswe/PS1dE9. TREM2-BAC mice were also crossed with APPswe/PS1dE9, a second mouse model of amyloidosis. 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
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
2. JAX MMRRC Stock# 034840

Further Reading