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Decoding TREM2 Signaling Pathways
Yanfei Che, Ziman Yu, Songjie Ji, Dan Yang. Neurology Neuroimmunology & Neuroinflammation, 2026-01-09
Topic: Brain proteins, microglia and lab models
Triggering receptor expressed on myeloid cells 2 (TREM2) is a key immunomodulatory receptor broadly expressed on myeloid cells such as macrophages and microglia. It plays versatile roles in neurodegenerative diseases, tissue repair, and tumor immunity by orchestrating glucose metabolism and inflammatory responses. This review systematically summarizes the structural characteristics of TREM2, its ligand-binding mechanisms, and downstream signaling pathways-including the phosphoinositide 3-kinase/protein kinase B(PI3K/Akt), mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription 3 (STAT3) cascades-with a particular focus on its central role in macrophage metabolic reprogramming.In neurodegenerative diseases such as Alzheimer disease, TREM2 contributes to the attenuation of neuroinflammation and slows disease progression by promoting β-amyloid (Aβ) clearance, inhibiting tau hyperphosphorylation, and modulating microglial polarization. Loss-of-function sequence variants, such as R47H, disrupt lipid metabolism, impair phagocytic activity, and destabilize immune homeostasis, thereby significantly increasing disease susceptibility. Furthermore, by enhancing glycolysis and suppressing fatty acid oxidation, TREM2 facilitates macrophage polarization toward a reparative M2 phenotype, promoting neuroregeneration and remyelination in conditions such as spinal cord injury and multiple sclerosis.Within the tumor microenvironment, TREM2 influences tumor progression and therapeutic resistance by modulating the metabolic reprogramming of tumor-associated macrophages (TAMs)-notably through activation of pyruvate kinase muscle isozyme M2 (PKM2)-dependent glycolysis-and promoting an immunosuppressive phenotype. In metabolic disorders such as diabetes and obesity, TREM2 exerts protective effects by inhibiting NLRP3 inflammasome activation and maintaining lipid homeostasis, highlighting its therapeutic potential.This review also outlines the translational prospects of TREM2 as a therapeutic target, including the development of agonists, gene regulatory strategies, and its potential use as a biomarker. Future studies should aim to elucidate the ligand-specific biased signaling and dynamic regulatory networks of TREM2 within tissue microenvironments to advance precision interventions in neuroimmunometabolic diseases.
Key findings
- Loss-of-function sequence variants, such as R47H, disrupt lipid metabolism, impair phagocytic activity, and destabilize immune homeostasis, thereby significantly increasing disease susceptibility.
Why it matters
This review describes how TREM2 signaling, including PI3K/Akt, MAPK, NF-κB, and STAT3 pathways, contributes to reducing neuroinflammation and slowing disease progression in Alzheimer's disease by promoting Aβ clearance and inhibiting tau hyperphosphorylation. It is a review of mechanisms, not a clinical trial, so it does not show that targeting TREM2 treats or cures Alzheimer's disease in people.
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Study details
- Evidence strengthLow
How this study scored 48/100
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. We have no data on senior author's track record, so that was left out: it earned 46 of the 96 points we could judge it on, which is 48 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurology Neuroimmunology & Neuroinflammation) |
| Journal's citation record | 1 / 4 | Neurology Neuroimmunology & Neuroinflammation: journal h-index 101 (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 | 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 | 3 / 7 | Cited 18 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 9.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 6 / 6 | Cited 45.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 18 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | OpenAlex's profile for last-listed author Dan Yang holds only 4 work(s), too few to judge a track record — left out of this score |
| Institution's track record | 1 / 3 | Chinese Academy of Medical Sciences & Peking Union Medical College: institution h-index 950 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41512220) |
| Free to read | 2 / 2 | Free to read |
| Points | 46 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 46 of the 96 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 →
Read the original
- DOI: 10.1212/nxi.0000000000200527
- PubMed: 41512220
- Original source →
- Free full text: Neurology Neuroimmunology & Neuroinflammation →
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. Check the citation against the original before you use it.
APA 7th
Che, Y., Yu, Z., Ji, S., & Yang, D. (2026). Decoding TREM2 Signaling Pathways. Neurology Neuroimmunology & Neuroinflammation. https://doi.org/10.1212/nxi.0000000000200527
Vancouver
Che Y, Yu Z, Ji S, Yang D. Decoding TREM2 Signaling Pathways. Neurology Neuroimmunology & Neuroinflammation. 2026. doi:10.1212/nxi.0000000000200527. PMID: 41512220.
BibTeX
@article{che2026-41512220,
author = {Che, Yanfei and Yu, Ziman and Ji, Songjie and Yang, Dan},
title = {{Decoding TREM2 Signaling Pathways}},
journal = {Neurology Neuroimmunology \& Neuroinflammation},
year = {2026},
doi = {10.1212/nxi.0000000000200527},
pmid = {41512220},
url = {https://doi.org/10.1212/nxi.0000000000200527}
}
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