Species: Mouse
Genes: Trem2
Mutations: TREM2 H157Y
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57Bl/6J
Availability: Available through Na Zhao (zhao.na@mayo.edu).

Summary

Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor found on microglia, where it modulates cell activity and survival. TREM2 is cleaved by ADAM proteases after amino acid 157 to release a soluble fragment, sTREM2, whose function is still being elucidated (Feuerbach et al., 2017; Schlepckow et al., 2017; Thornton et al., 2017; 31 Aug 2017 news). H157Y is a rare TREM2 variant that was shown, in vitro, to increases the generation of sTREM2 (Schlepckow et al., 2017; Thornton et al., 2017). The variant first gained attention when it was found to associate with an increased risk for Alzheimer’s disease (AD) in a Han Chinese cohort (Jiang et al., 2016a). Subsequent analyses of cohorts of multiple ancestries confirmed an association (Jiang et al., 2016b; Song et al., 2017), although it should be noted that a large case-control study of Caucasians did not (Sims et al., 2017).

Trem2-H157Y knock-in mice were created by CRISPR/Cas9 gene editing (Qiao et al., 2023), allowing scientists to study the effects of the variant in vivo. As predicted by the findings in vitro, elevated levels of sTREM2 were found in mice homozygous for the variant, compared with littermates expressing wild-type Trem2. The H157Y mutation did not affect microglial density or morphology, performance on a battery of behavioral tests, or levels of synaptic markers, but enhanced hippocampal synaptic plasticity. When Trem2-H157Y mice were crossed with 5xFAD mice, a model of aggressive amyloidosis, the Trem2 variant decreased amyloid pathology, microgliosis and plaque-associated neuritic damage. Such ameliorating effects on amyloid-related pathology seem counterintuitive for a variant that increases AD risk and point toward the need to study the effects of the H157Y variant in other AD-related models, including tauopathy models.

TREM2 levels and activity | Microglia | Synapse number and function | Cognitive function | Transcriptomics | Modification details | Related Models

TREM2 levels and activity

Levels of Trem2 mRNA did not differ between Trem2^+/+, Trem2^+/H157Y, and Trem2^H157Y/H157Y littermates, as assessed by qPCR of cortical samples from 6-month-old animals.

Three lines of evidence indicated that levels of sTREM2 were elevated in Trem2^H157Y/H157Y, compared with the other two genotypes. First, cortical samples were subjected to a sequential process in which soluble proteins were first extracted into Tris-buffered saline (TBS), then membrane-associated proteins were extracted into TBS containing the detergent Triton X-100 (TBS-T). TREM2 in these fractions was then measured by ELISA. Levels of TREM2 in the TBS fraction—presumably sTREM2—were higher in Trem2^H157Y/H157Y mice than Trem2^+/+ or Trem2^+/H157 animals. Second, levels of TREM2 in the sera of homozygotes were higher than in wild-type mice, with levels in heterozygotes falling in between but not significantly different than the other two genotypes. Finally, levels of TREM2 were higher in the conditioned media of microglia cultured from neonatal Trem2^H157Y/H157Y mice than conditioned media from Trem2^+/+ or Trem2^+/H157 microglia.

The increase in sTREM2 was not accompanied by a measurable decrease in the level of membrane-associated TREM2 or a reduction in TREM2 signaling. The amount of TREM2 in the TBS-T fractions of cortical samples did not differ between genotypes, nor did the levels of TREM2 in detergent-containing extracts of microglia cultured from the mice. The protein tyrosine kinase SYK acts downstream of TREM2 in a signaling cascade, and levels of activated SYK did not differ between microglia acutely isolated from Trem2^H157Y/H157Y, Trem2^+/H157, or Trem2^+/+ mice. These findings contrast with previously reported results in HEK cells transfected with TREM2, where the H157Y variant resulted in less TREM2 on the cell surface (Schlepckow et al., 2017) and reduced TREM2 signaling (Song et al., 2017).

Microglia

Microglial density and morphology did not differ between genotypes.

Synapse number and function

Levels of the presynaptic marker synaptophysin and the postsynaptic markers PSD95 and GLUR2 in the cortices of 6-month-old mice did not differ between genotypes.

Electrophysiological recordings of activity at Schaffer collateral-CA1 synapses were obtained in slices from 6-month-old mice homozygous for the wild-type or H157Y Trem2 alleles. Trem2^+/+ and Trem2^H157Y/H157Y mice did not differ in basal synaptic transmission, but stronger paired-pulse facilitation (PPF) and long-term potentiation (LTP) were observed in H157Y carriers.

Cognitive function

The H157Y mutation did not affect the performances of 6-month-old mice on a battery of behavioral tests: the open-field test to assess anxiety, cued and contextual fear conditioning to measure associative memory, and the Y-maze test to measure spatial working memory.

Transcriptomics

Bulk RNA sequencing revealed only three differentially expressed genes in the cortices of 6-month-old Trem2^H157Y/H157Y mice compared with wild-type animals: Treml2, Pot1b, Srsf5.

Modification details

CRISPR/Cas9 gene editing was used to introduce the H157Y mutation into the mouse Trem2 gene.

Related Models

The following models have been used to manipulate levels of soluble TREM2, through genetic alteration of the ADAM protease cleavage site or AAV-mediated expression of an extracellular fragment of TREM2.

Trem2-H157Y x 5xFAD. Trem2-H157Y mice were intercrossed with 5xFAD mice, a model of aggressive amyloidosis. Levels of Trem2 mRNA and TREM2 protein—both full-length, membrane-associated TREM2 and sTREM2—were lower in 5xFAD mice homozygous for Trem2-H157Y, compared with 5xFAD mice expressing wild-type Trem2. This difference may reflect the lower number of microglia in the brains of the Trem2 mutation carriers. However, the ratio of sTREM2 to full-length TREM2 was higher in the Trem2 mutation carriers, consistent with increased shedding of TREM2-H157Y.

Compared with 5xFAD mice homozygous for wild-type Trem2, mice homozygous for the H157Y variant showed age-dependent decreases in plaque burdens, microgliosis and plaque-associated neuritic damage. At 8.5 months, the only timepoint reported to date, expression of neuroinflammation-related genes was downregulated in the H157Y mutation carriers.

TREM2-sol. In an attempt to create a model that generates only sTREM2—but no full-length, signaling-competent receptor—CRISPR/Cas9 gene editing was used to introduce a stop codon after H157 of murine Trem2. These mice, called “TREM2-sol,” were found to express very low levels of sTREM2 and Trem2 mRNA. Nonetheless, differences between TREM2-sol and Trem2 knockout mice (Trem2-KO) were observed, including prolonged microglial responses to injury, increased vulnerability of bone marrow-derived macrophages to growth factor deprivation, and preservation of endo-lysosomal function in TREM2-sol compared with Trem2-KO mice.

TREM2-IPD. CRISPR/Cas9 gene editing was used to disrupt the ADAM10/17 recognition site on mouse TREM2, changing histidine-157 to isoleucine (I), serine-158 to proline (P), and threonine-159 to aspartate (D)—leading to both a reduction in sTREM2 and an increase in cell-surface TREM2. The IPD mutation accelerated microglial maturation and increased microglial phagocytic activity. In the cuprizone model of demyelination, the mutation resulted in persistent neuroinflammation during the recovery phase.

TREM2-IPDxAPP23xPS45. To study the effects of reducing TREM2 cleavage in the context of amyloid pathology, TREM2-IPD mice were intercrossed with APP23 and PS45 mice (Herzig et al., 2004), which carry transgenes for human APP with the AD-linked Swedish mutation and PSEN1 with the AD-linked G384A mutation, respectively. Compared with APP23xPS45 mice carrying wild-type Trem2, TREM2-IPDxAPP23xPS45 mice had higher plaque burdens and more severe plaque-associated pathology at an early—but not late—stage of plaque deposition.

AAV-sTREM2 5xFAD. AAV-sTREM2 5xFAD mice were created to study the long-term effects of soluble TREM2 (sTREM2) in the context of amyloidosis. To generate this model, AAV carrying cDNA encoding EGFP- and FLAG-tagged sTREM2 (amino acids 1-171 of human TREM2) was injected into the brains of neonatal 5xFAD mice. Overexpression of sTREM2 led to decreased plaque burdens, increased the number of plaque-associated microglia, and rescued hippocampal long-term potentiation and performance in the Morris water maze in 5xFAD mice aged 6 to 7 months.

AAV-sTREM2 PS19. AAV-sTREM2 PS19 mice were created to study the long-term effects of soluble TREM2 (sTREM2) in the context of tauopathy. To generate this model, AAV carrying cDNA encoding EGFP- and FLAG-tagged sTREM2 (amino acids 1-171 of human TREM2) was injected into the brains of 3-month-old PS19 mice. AAV-mediated expression of sTREM2 protected against hippocampal synapse loss, improved performance in the Morris water maze and Y-maze, enhanced long-term potentiation, and reduced levels of p-tau202 and p-tau396 in PS19 mice studied at 7 months of age.

Phenotype Characterization

Complementary Models

The effects of the TREM2 H157Y variant on TREM2 cleavage were initially studied in non-myeloid cells engineered to over express TREM2. In HEK293 cells stably (Schlepckow et al., 2017) or transiently (Thornton et al., 2017) transfected with TREM2 constructs, the H157Y variant led to increased TREM2 shedding and less cell-surface TREM2, compared with wild-type TREM2. The variant was also found to reduce phagocytosis of E.coli particles by HEK cells (Schlepckow et al., 2017).

The effect of the H157Y variant on TREM2 activation was studied in a myeloid cell line (2B4 T cells) engineered to turn on GFP expression when intracellular Ca²⁺ levels rise, a downstream consequence of TREM2 signaling. Retroviral transduction was used to stably insert TREM2—either the H157Y variant or the common variant—and its adaptor DAP12 into these reporter cells, and it was found that the H157Y variant reduced activation in response to phospholipid ligands (Song et al., 2017).

The H157Y mutation has been introduced into the Trem2 gene in BV2 cells—a mouse microglial cell line—by CRISPR/Cas9 gene editing (Fu et al., 2023). Compared with parental BV2 cells expressing wild-type mouse Trem2, BV2-H157Y cells showed an approximate 50 percent decrease in the uptake of Aβ42. Expression of the H157Y variant also appeared to promote a stronger shift towards an inflammatory state when BV2 cells were stimulated with LPS: Upon stimulation with LPS, both Trem2 genotypes increased production of iNOS and released the inflammatory cytokines IL-1β, IL-6, and TNF-α, but the response of BV2-H157Y cells was greater than wild-type. Conversely, LPS stimulation decreased levels of ARG1 and CD206—considered markers of an anti-inflammatory microglial phenotype—in BV2-H157Y cells while not affecting these markers in wild-type cells. These in vitro findings contrast with the effects of the H157Y mutation in vivo in a different pro-inflammatory environment: When Trem2-H157Y mice were crossed with 5xFAD mice, a model of aggressive amyloidosis, the Trem2 variant decreased amyloid pathology and led to downregulation of genes encoding inflammatory cytokines, compared with 5xFAD mice expressing wild-type Trem2 (Qiao et al., 2023).

Q&A with Model Creator

Q&A with Wenhui Qiao and Na Zhao.

What would you say are the unique advantages of this model? This model is the first animal model to feature a knock-in of the Trem2 H157Y mutation, enabling the study of how this mutation influences TREM2-related functions.

What do you think this model is best used for? This model can be used to understand TREM2's overall function, particularly how increased soluble TREM2 due to the H157Y mutation influences microglial functions.

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References

News Citations

1. TREM2 Cleavage Site Pinpointed: A Gateway to New Therapies? 31 Aug 2017

Research Models Citations

1. Trem2-H157Y x 5xFAD
2. 5xFAD (C57BL6)
3. TREM2-sol
4. Trem2 KO (KOMP)
5. TREM2-IPD
6. Trem2-IPDxAPP23xPS45
7. APP23
8. AAV-sTREM2 5xFAD
9. AAV-sTREM2 PS19
10. Tau P301S (Line PS19)
11. Trem2-H157Y knock-in
12. Trem2-H157Y x 5xFAD
13. 5xFAD (C57BL6)

Mutations Citations

1. APP K670_M671delinsNL (Swedish)
2. PSEN1 G384A
3. TREM2 H157Y

Paper Citations

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Further Reading

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