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Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease
Ellwanger DC, Wang S, Brioschi S, Shao Z, Green L, Case R, Yoo D, Weishuhn D et al.. Proceedings of the National Academy of Sciences of the United States of America, 2021-01-01
Topic: Brain proteins, microglia and lab models
Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer's disease (AD) risk is associated with the TREM2 R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant ( TREM2 CV ) or TREM2 R47H scRNA-seq of microglia from TREM2 CV -5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types.
Key findings
- Alzheimer's disease (AD) risk is associated with the TREM2 R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology.
- Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant ( TREM2 CV ) or TREM2 R47H scRNA-seq of microglia from TREM2 CV -5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types.
- All of these were underrepresented in TREM2 R47H -5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories.
- Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2 CV -5XFAD mice, likely due to greater Aβ load in female 5XFAD mice.
Why it matters
In 5XFAD mice, engaging TREM2 with the antibody hT2AB activated microglia, and the R47H variant impaired ligand binding and microglial responses to amyloid-β pathology. This is mouse work testing a tool antibody and does not demonstrate a treatment for people.
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Study details
- Evidence strengthLow
How this study scored 52/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America) |
| Journal's citation record | 4 / 4 | Proceedings of the National Academy of Sciences: journal h-index 1,167 (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 | 3 / 5 | 2021 — within 6 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 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 141 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 20.1 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 3 / 6 | Cited 7.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 21 other studies in this library |
| Still being cited | 3 / 4 | Cited 72 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Marco Colonna: h-index 172 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33446504) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 52 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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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
Ellwanger, D. C., Wang, S., Brioschi, S., Shao, Z., Green, L., Case, R., et al. (2021). Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2017742118
Vancouver
Ellwanger DC, Wang S, Brioschi S, Shao Z, Green L, Case R, et al. Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America. 2021. doi:10.1073/pnas.2017742118. PMID: 33446504.
BibTeX
@article{ellwanger2021-33446504,
author = {Ellwanger, D. C. and Wang, S. and Brioschi, S. and Shao, Z. and Green, L. and Case, R. and Yoo, D. and Weishuhn, D. and others},
title = {{Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer's disease}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2021},
doi = {10.1073/pnas.2017742118},
pmid = {33446504},
url = {https://doi.org/10.1073/pnas.2017742118}
}
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