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Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model
Andrew J. Boreland, Yara Abbo, Xindi Li, Alessandro C. Stillitano, Siwei Zhang, Jubao Duan, Zhiping P. Pang, Ronald P. Hart. Alcohol, 2025-11-07
Topic: Brain proteins, microglia and lab models
Alcohol use disorders (AUDs) affect substantial populations worldwide and increase the risk of developing cognitive impairments and alcohol-associated dementia. While chronic inflammatory signaling likely plays an important role in alcohol-associated neurological sequalae, the precise mechanisms underlying alcohol-associated neuropathology remain enigmatic. We hypothesize that alcohol leads to neuroimmune dysregulation among neurons, astrocytes, and microglia; and is perpetuated by innate immune signaling pathways involving cell-cell signaling. To investigate how alcohol dysregulates neuroimmune interactions in a human context, we constructed a triculture model comprising neurons, astrocytes, and microglia derived from human induced pluripotent stem cells. After exposure to ethanol, we observed significant differential gene expression relating to innate immune pathways, inflammation, and microglial activation. Microglial activation was confirmed with morphological analysis and expression of CD68, a lysosomal-associated membrane protein and marker for phagocytic microglial activation. A striking finding in our study was the elevation of TREM2 expression and, specifically, TREM2 alternatively spliced isoforms that are predicted to give rise to soluble TREM2. TREM2 loss-of-function variants have been reported to be a risk factor for Alzheimer’s disease. These results suggest that ethanol exposure in the brain may lead to increased microglial activation and production of soluble isoform named TREM2 219 through alternate splicing. Deciphering the molecular and cellular mechanisms underpinning ethanol-related neuroimmune dysregulation within a human context promises to shed light on the etiology of AUD-related disorders, potentially contributing to the development of effective therapeutic strategies.
Key findings
- After exposure to ethanol, we observed significant differential gene expression relating to innate immune pathways, inflammation, and microglial activation.
- These results suggest that ethanol exposure in the brain may lead to increased microglial activation and production of soluble isoform named TREM2 219 through alternate splicing.
Why it matters
In a human cell model of neurons, astrocytes, and microglia, ethanol exposure caused immune-related gene changes, microglial activation, and increased production of a soluble form of TREM2. This is a laboratory model of alcohol-related neuroimmune dysregulation, not a finding about treating or preventing Alzheimer's disease.
Study details
- Evidence strengthLow
How this study scored 39/100
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 (Alcohol) |
| Journal's citation record | 1 / 4 | Alcohol: journal h-index 116 (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 | 4 / 5 | 2025 — within 3 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 “ipsc”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Ronald P. Hart: h-index 54 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Chicago: institution h-index 1,769 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41205777) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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 names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Boreland, A. J., Abbo, Y., Li, X., Stillitano, A. C., Zhang, S., Duan, J., et al. (2025). Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model. Alcohol. https://doi.org/10.1016/j.alcohol.2025.10.006
Vancouver
Boreland AJ, Abbo Y, Li X, Stillitano AC, Zhang S, Duan J, et al. Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model. Alcohol. 2025. doi:10.1016/j.alcohol.2025.10.006. PMID: 41205777.
BibTeX
@article{boreland2025-41205777,
author = {Boreland, Andrew J. and Abbo, Yara and Li, Xindi and Stillitano, Alessandro C. and Zhang, Siwei and Duan, Jubao and Pang, Zhiping P. and Hart, Ronald P.},
title = {{Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model}},
journal = {Alcohol},
year = {2025},
doi = {10.1016/j.alcohol.2025.10.006},
pmid = {41205777},
url = {https://doi.org/10.1016/j.alcohol.2025.10.006}
}
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