Home › Research › Risk genes beyond APOE
Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage
Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J.. The Journal of biological chemistry, 2013-09-27
Topic: Brain proteins, microglia and lab models
Triggering receptor expressed on myeloid cells-2 (TREM2) and its signaling adaptor protein TYROBP/DAP12 play important roles in signal transduction in dendritic cells, osteoclasts, tissue macrophages, and microglia. Recently, TREM2 variants have been shown to be linked to late onset Alzheimer disease. Here, we demonstrate that TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis.
Key findings
- Recently, TREM2 variants have been shown to be linked to late onset Alzheimer disease.
- Here, we demonstrate that TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis.
- The C-terminal fragment (CTF) of TREM2 generated by ectodomain shedding is cleaved by γ-secretase.
- Importantly, pharmacologic and genetic γ-secretase inhibition resulted in accumulation of TREM2 CTF at the plasma membrane that also interacts with the signaling adaptor protein DAP12.
Why it matters
TREM2 is a receptor on immune cells, including the brain's microglia, and variants in its gene have been linked to late-onset Alzheimer's disease. This laboratory study reports that TREM2 is cut in two steps: its outer part is first shed from the cell surface, and the stub left in the membrane is then cut by the enzyme γ-secretase. When γ-secretase was blocked by a drug or genetically, the stub built up at the cell surface and still bound its signalling partner DAP12; the study tested no treatment and did not study patients.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 48/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of biological chemistry) |
| Journal's citation record | 4 / 4 | Journal of Biological Chemistry: journal h-index 780 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2013 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 295 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 19.7 citations a year over 15 year(s) since 2013 |
| Impact for its field and year | 4 / 6 | Cited 8.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 84 other studies in this library |
| Still being cited | 3 / 4 | Cited 75 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Jochen Walter: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Bonn: institution h-index 1,072 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 24078628) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 48 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1074/jbc.m113.517540
- PubMed: 24078628
- Original source →
- Free full text: Journal of Biological Chemistry →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., Neumann, H., & Walter, J. (2013). Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage. The Journal of biological chemistry. https://doi.org/10.1074/jbc.m113.517540
Vancouver
Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J. Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage. The Journal of biological chemistry. 2013. doi:10.1074/jbc.m113.517540. PMID: 24078628.
BibTeX
@article{wunderlich2013-24078628,
author = {Wunderlich, P. and Glebov, K. and Kemmerling, N. and Tien, N. T. and Neumann, H. and Walter, J.},
title = {{Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and γ-secretase-dependent intramembranous cleavage}},
journal = {The Journal of biological chemistry},
year = {2013},
doi = {10.1074/jbc.m113.517540},
pmid = {24078628},
url = {https://doi.org/10.1074/jbc.m113.517540}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 15.
Later studies that cite this one
84 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Risk genes beyond APOE
Also tagged “macrophages”
363 studies in the library carry the topic tag “macrophages”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 363 tagged studies.