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TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism
Astrid F Feiten, Kilian Dahm, Kai Schlepckow, Bettina van Lengerich, Jung H Suh, Anika Reifschneider, Benedikt Wefers, Laura M Bartos et al.. Nature communications, 2026-01-24
Topic: Inflammation, microglia and astrocytes
Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and loss-of-function coding variants are major risk factors for late onset Alzheimer's disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse. In APP transgenic animals, bulk RNA-sequencing of isolated microglia sorted based on reporter expression highlighted TREM2 level-related changes in major immunometabolic pathways, and enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis. In accordance, metabolic activity correlated with phagocytic capacity. Finally, we performed chronic treatment with a TREM2 agonist antibody and identified a window of TREM2 expression where microglia are most responsive, thereby informing clinical applications of TREM2 agonists.
Key findings
- To better understand the molecular and functional changes associated with TREM2 signalling in microglia, we generated a TREM2 reporter mouse.
- Metabolic and lipidomic profiling of sorted microglia showed that, independent of Aβ pathology, TREM2 expression correlated with signatures consistent with increased cellular redox, energetics, and cholesterol homoeostasis.
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Study details
- Evidence strengthLow
How this study scored 48/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 27 of the 56 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature communications) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 5 / 5 | 2026 — within 1 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41580393) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 27 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 27 of the 56 points we could judge it on is 48 out of 100. |
| Total | 48 / 100 | — |
What each of these 20 components measures, and what this score is not →
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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
Feiten, A. F., Dahm, K., Schlepckow, K., van Lengerich, B., Suh, J. H., Reifschneider, A., et al. (2026). TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism. Nature communications. https://doi.org/10.1038/s41467-026-68706-8
Vancouver
Feiten AF, Dahm K, Schlepckow K, van Lengerich B, Suh JH, Reifschneider A, et al. TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism. Nature communications. 2026. doi:10.1038/s41467-026-68706-8. PMID: 41580393.
BibTeX
@article{feiten2026-41580393,
author = {Feiten, Astrid F and Dahm, Kilian and Schlepckow, Kai and van Lengerich, Bettina and Suh, Jung H and Reifschneider, Anika and Wefers, Benedikt and Bartos, Laura M and others},
title = {{TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism}},
journal = {Nature communications},
year = {2026},
doi = {10.1038/s41467-026-68706-8},
pmid = {41580393},
url = {https://doi.org/10.1038/s41467-026-68706-8}
}