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Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology
Yuan Xu, Ya Peng, Feng Zhi, Yilin Yang, Jiahui Li, Ligang Fan, Ying Xia, Nan Shao. Brain Behavior and Immunity, 2025-10-24
Topic: Brain proteins, microglia and lab models
While previous studies have well established δ-opioid receptor (DOR)-mediated neuroprotection against Alzheimer's pathology, the underlying mechanisms remain poorly understood. Our present work reveals a strong negative correlation between DOR and the classical complement pathway (CCP) initiator C1q, confirming their direct binding both in vitro and in APP/PS1 transgenic mice. Activating DOR with the specific agonist UFP-512 in aged APP/PS1 mice reduced cerebral C1q levels, while increasing DOR-C1q binding affinity. This interaction subsequently suppressed CCP activation, ameliorated complement-dependent synaptic engulfment by microglia, prevented synaptic protein loss, and consequently improved cognitive performance of these Alzheimer's disease (AD) mice. Consistent with these findings, overexpressing microglial DOR effectively inhibited its shift towards a phagocytotic phenotype and protected co-cultured neurons from lipopolysaccharide (LPS) -induced injury. Collectively, our findings demonstrate a critical role of DOR in restricting complement-mediated synaptic elimination during neurodegeneration, highlighting its potential as a new therapeutic target for AD.
Key findings
- Consistent with these findings, overexpressing microglial DOR effectively inhibited its shift towards a phagocytotic phenotype and protected co-cultured neurons from lipopolysaccharide (LPS) -induced injury.
- Collectively, our findings demonstrate a critical role of DOR in restricting complement-mediated synaptic elimination during neurodegeneration, highlighting its potential as a new therapeutic target for AD.
Why it matters
In mice with Alzheimer's-like pathology, activating the delta-opioid receptor reduced C1q levels, limited microglia-mediated synapse loss and improved cognitive performance. These are animal and cell results, so it is not yet known whether the same approach would work in people.
Study details
- Evidence strengthLow
How this study scored 36/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Brain Behavior and Immunity) |
| Journal's citation record | 2 / 4 | Brain Behavior and Immunity: journal h-index 249 (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 | 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 | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.1× 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 | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Nan Shao: h-index 36 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Fudan University: institution h-index 954 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41138884) |
| Free to read | 2 / 2 | Free to read |
| Total | 36 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1016/j.bbi.2025.106149
- PubMed: 41138884
- Original source →
- Free full text: Brain Behavior and Immunity →
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
Xu, Y., Peng, Y., Zhi, F., Yang, Y., Li, J., Fan, L., et al. (2025). Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology. Brain Behavior and Immunity. https://doi.org/10.1016/j.bbi.2025.106149
Vancouver
Xu Y, Peng Y, Zhi F, Yang Y, Li J, Fan L, et al. Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology. Brain Behavior and Immunity. 2025. doi:10.1016/j.bbi.2025.106149. PMID: 41138884.
BibTeX
@article{xu2025-41138884,
author = {Xu, Yuan and Peng, Ya and Zhi, Feng and Yang, Yilin and Li, Jiahui and Fan, Ligang and Xia, Ying and Shao, Nan},
title = {{Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology}},
journal = {Brain Behavior and Immunity},
year = {2025},
doi = {10.1016/j.bbi.2025.106149},
pmid = {41138884},
url = {https://doi.org/10.1016/j.bbi.2025.106149}
}
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