TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer's disease‐associated H157Y variant
Open accessAbstract
We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2‐expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N‐terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding. Peptidomimetic protease inhibitors highlighted a possible cleavage site, and mass spectrometry confirmed that shedding occurred predominantly at the H157‐S158 peptide bond for both wild‐type and H157Y human TREM2 and for the wild‐type murine orthologue. Crucially, we also show that the Alzheimer's disease‐associated H157Y TREM2 variant was shed more rapidly than wild type from HEK293 cells, possibly by a novel, batimastat‐ and ADAM10‐siRNA‐independent, sheddase activity. These insights offer new therapeutic targets for modulating the innate immune response in Alzheimer's and other neurological diseases.
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TREM2 p.H157Y increases shedding from microglia, leading to phagocytosis deficits.
“Increased shedding from microglia [45], leading to phagocytosis deficits [46]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [45]
The Results section reports that H157Y increases TREM2 shedding, but that comparison was performed in HEK293 cells, not microglia. The paper separately reports TREM2 shedding from murine microglia. The phagocytosis-deficit clause is attached to a different citation, so it is not judged here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredp.H157Y increases shedding.
“and increased shedding (p.H157Y [45], Table 1)”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [45]
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TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation
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“It is noteworthy that a high-molecular-weight smear is detected for all three sTREM2 species, suggesting robust glycosylation of sTREM2, which has been previously described [12, 47].”
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Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages
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PET imaging of microglia in Alzheimer's disease using copper-64 labeled TREM2 antibodies
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Variant TREM2 Signaling in Alzheimer's Disease
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Regulation of Leukocytes by TspanC8 Tetraspanins and the “Molecular Scissor” ADAM10
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Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology
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TREM2-expressing macrophages in liver diseases
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APOEε4 and risk of Alzheimer’s disease – time to move forward
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- Authors
- Thornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez‐Nievas, B., Nicol, L. S., Eketjäll, S., Revell, J., Jones, C., Billinton, A., St George‐Hyslop, P. H., Chessell, I., & Crowther, D. C.
- Affiliations
- AstraZeneca (United Kingdom) (GB)
- University of Cambridge (GB)
- University of Toronto (CA)
- Karolinska Institutet (SE)
- Integrated Cardio Metabolic Centre (SE)
- Corresponding author
- Crowther, Damian C
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2017-08-30
- Volume
- 9
- Issue
- 10
- Pages
- 1366-1378
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC5623839
- OpenAlex
- W2753509052
- Cited by
- 200
- References
- 33
- Citations by year
- 2026: 29 · 2025: 34 · 2024: 18 · 2023: 37 · 2022: 17 · 2021: 18 · 2020: 16 · 2019: 14 · 2018: 15 · 2017: 2
- FWCI
- 6.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome
- Canadian Institute of Health Research
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- TREM2, Alzheimer's disease, protein shedding, proteolytic cleavage, ADAM10, metalloproteinase inhibitors, microglia, macrophages, innate immune response, therapeutic target
- MeSH terms
- ADAM10 Protein, ADAM17 Protein, Alzheimer Disease, Animals, Animals, Newborn, Humans, Ketocholesterols, Macrophages, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred C57BL, Receptors, Immunologic, Culture Media, Conditioned, Microglia, RNA, Small Interfering, Mice, Amyloid Precursor Protein Secretases, HEK293 Cells, Proteolysis, Primary Cell Culture, Matrix Metalloproteinase Inhibitors
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