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Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G et al.. EMBO molecular medicine, 2020-03-10
Topic: Brain proteins, microglia and lab models
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding.
Key findings
- To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17.
- We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding.
- Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β-peptide in vitro.
- In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound.
Why it matters
Researchers screened antibodies against TREM2, a receptor on the brain's immune cells, looking for one that stops enzymes from cutting it off the cell surface. One antibody, 4D9, both kept TREM2 on the cell surface and "concomitantly" switched on its internal signalling, helped macrophages survive, and in a living-animal test bound "nearly all soluble TREM2" in cerebrospinal fluid. This shows the antibody reaches its target in the lab and in vivo. It does not show any effect on Alzheimer's pathology or symptoms.
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Study details
- Evidence strengthLow
How this study scored 54/100
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 | 2020 — 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 | 6 / 7 | Cited 321 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 40.1 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 4 / 6 | Cited 14.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 49 other studies in this library |
| Still being cited | 3 / 4 | Cited 144 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 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 32154671) |
| Free to read | 2 / 2 | Free to read |
| Total | 54 / 100 | — |
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Read the original
- DOI: 10.15252/emmm.201911227
- PubMed: 32154671
- 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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti-Castelvetri, L., Parhizkar, S., Xia, D., et al. (2020). Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO molecular medicine. https://doi.org/10.15252/emmm.201911227
Vancouver
Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, et al. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO molecular medicine. 2020. doi:10.15252/emmm.201911227. PMID: 32154671.
BibTeX
@article{schlepckow2020-32154671,
author = {Schlepckow, K. and Monroe, K. M. and Kleinberger, G. and Cantuti-Castelvetri, L. and Parhizkar, S. and Xia, D. and Willem, M. and Werner, G. and others},
title = {{Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region}},
journal = {EMBO molecular medicine},
year = {2020},
doi = {10.15252/emmm.201911227},
pmid = {32154671},
url = {https://doi.org/10.15252/emmm.201911227}
}
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