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Soluble TREM2 suppresses neuronal activity
Zott B, Unger F, Wolf C, Schlepckow K, Ulmer N, Rossignol P, Pousinha P, Chen L et al.. Research Square, 2026-10-28
Topic: Inflammation, microglia and astrocytes
Neuronal activity must be tightly controlled to maintain brain function. Accumulating evidence identifies microglia as regulators of neuronal activity. The triggering receptor expressed on myeloid cells 2 (TREM2) shapes microglial states and is implicated in brain disorders, including Alzheimer’s disease (AD). Cleavage of TREM2 releases its ectodomain, soluble TREM2 (sTREM2), which has been linked to protective effects, but whose binding partners and mechanisms of action remain incompletely understood. Here, we asked whether sTREM2 directly influences neuronal and circuit activity in vivo. Using mouse models and in vitro systems, we demonstrate that sTREM2 rapidly and reversibly suppresses neuronal activity at both single-cell and circuit levels in the healthy brain. Mechanistically, sTREM2 engages purinergic microglia–neuron signaling by binding CD73, the ectoenzyme converting AMP to adenosine. Elevated sTREM2 levels protect against kainic-acid (KA) induced epileptic seizures and prevent β-amyloid (Aβ)-dependent neuronal hyperactivation. These findings establish a physiological role of sTREM2 as a fast-acting modulator of neuronal activity. In addition, by limiting aberrant circuit activity induced by KA or Aβ, sTREM2 may protect against excitotoxicity and constitute a potential target for disease-modifying therapies.
Key findings
- These findings establish a physiological role of sTREM2 as a fast-acting modulator of neuronal activity.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. 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 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 and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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
Zott, B., Unger, F., Wolf, C., Schlepckow, K., Ulmer, N., Rossignol, P., et al. (2026). Soluble TREM2 suppresses neuronal activity. Research Square. https://doi.org/10.21203/rs.3.rs-11388834/v1
Vancouver
Zott B, Unger F, Wolf C, Schlepckow K, Ulmer N, Rossignol P, et al. Soluble TREM2 suppresses neuronal activity. Research Square. 2026. doi:10.21203/rs.3.rs-11388834/v1.
BibTeX
@article{zott2026-90b7bcf3,
author = {Zott, B. and Unger, F. and Wolf, C. and Schlepckow, K. and Ulmer, N. and Rossignol, P. and Pousinha, P. and Chen, L. and others},
title = {{Soluble TREM2 suppresses neuronal activity}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11388834/v1},
url = {https://doi.org/10.21203/rs.3.rs-11388834/v1}
}