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An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function
Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C.. EMBO molecular medicine, 2017-10-01
Topic: Brain proteins, microglia and lab models
Sequence variations occurring in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) support an essential function of microglia and innate immunity in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane. Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis.
Key findings
- TREM2 matures within the secretory pathway, and its ectodomain is shed on the plasma membrane.
- Missense mutations in the immunoglobulin (Ig)-like domain such as p.T66M and p.Y38C retain TREM2 within the endoplasmic reticulum and reduce shedding as well as TREM2-dependent phagocytosis.
- Using mass spectrometry, we have now determined the cleavage site of TREM2.
- TREM2 is shed by proteases of the ADAM (a disintegrin and metalloproteinase domain containing protein) family C-terminal to histidine 157, a position where an AD-associated coding variant has been discovered (p.H157Y) in the Han Chinese population.
Why it matters
Using mass spectrometry, this laboratory study mapped where TREM2 (the "triggering receptor expressed on myeloid cells 2", which the authors tie to microglia and innate immunity in Alzheimer's) is cut and released from the cell surface: ADAM-family enzymes cut it just after amino acid histidine 157. That is the same position as p.H157Y, a variant the authors describe as Alzheimer-associated and found in the Han Chinese population, and the title says the variant "affects shedding and phagocytic function", although the stored record does not say in which direction. It is basic protein research with no patients and no treatment tested, so it explains a mechanism rather than showing a risk test or therapy.
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Study details
- Evidence strengthLow
How this study scored 53/100
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 (EMBO molecular medicine) |
| Journal's citation record | 2 / 4 | EMBO Molecular Medicine: journal h-index 186 (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 | 2 / 5 | 2017 — within 10 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 261 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 23.7 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 4 / 6 | Cited 8.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 58 other studies in this library |
| Still being cited | 3 / 4 | Cited 97 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Christian Haass: h-index 139 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Ludwig-Maximilians-Universität München: institution h-index 1,224 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28855300) |
| Free to read | 2 / 2 | Free to read |
| Total | 53 / 100 | — |
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Read the original
- DOI: 10.15252/emmm.201707672
- PubMed: 28855300
- Original source →
- Free full text: EMBO Molecular Medicine →
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. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., et al. (2017). An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO molecular medicine. https://doi.org/10.15252/emmm.201707672
Vancouver
Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO molecular medicine. 2017. doi:10.15252/emmm.201707672. PMID: 28855300.
BibTeX
@article{schlepckow2017-28855300,
author = {Schlepckow, K. and Kleinberger, G. and Fukumori, A. and Feederle, R. and Lichtenthaler, S. F. and Steiner, H. and Haass, C.},
title = {{An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function}},
journal = {EMBO molecular medicine},
year = {2017},
doi = {10.15252/emmm.201707672},
pmid = {28855300},
url = {https://doi.org/10.15252/emmm.201707672}
}
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