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Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis
Yixun Su, Hui Li, Wenjie Zhang, Shi Tao, Qi Wang, Xuan Zhang, Mi Zhou, Xiaomin Huang et al.. Nature Communications, 2025-07-01
Topic: Brain proteins, microglia and lab models
Alzheimer’s disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APPswe/PS1dE9 (APP/PS1) mouse model of amyloidosis, we demonstrated that microglial Cx43 hemichannels correlated with microglial malfunction, which in turn exacerbated β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifts microglia to a neuroprotective phenotype, enhancing the microglia-plaque interaction while suppressing neurotoxicity, thereby mitigating the progression of AD-like pathology. We developed TAT-Cx43@LNPs, a Cx43 hemichannel-targeting peptide delivered by a lipid nanoparticle system, which effectively delayed and rescued β-amyloid-related neuropathology and cognitive impairment in APP/PS1 mice. This study provides evidence for advancing Cx43 hemichannel targeting therapy into clinical trials. Microglia play a critical role in Alzheimer’s disease progression. Here, the authors show that knockout of microglial Cx43 or inhibition of Cx43 hemichannels by nanoparticle-delivered peptide mitigates cognitive deficits and neuropathology in APP/PS1 mice by inducing microglia into a neuroprotective state.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Su, Y., Li, H., Zhang, W., Tao, S., Wang, Q., Zhang, X., et al. (2025). Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis. Nature Communications. https://doi.org/10.1038/s41467-025-60746-w
Vancouver
Su Y, Li H, Zhang W, Tao S, Wang Q, Zhang X, et al. Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis. Nature Communications. 2025. doi:10.1038/s41467-025-60746-w. PMID: 40595567.
BibTeX
@article{su2025-40595567,
author = {Su, Yixun and Li, Hui and Zhang, Wenjie and Tao, Shi and Wang, Qi and Zhang, Xuan and Zhou, Mi and Huang, Xiaomin and others},
title = {{Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis}},
journal = {Nature Communications},
year = {2025},
doi = {10.1038/s41467-025-60746-w},
pmid = {40595567},
url = {https://doi.org/10.1038/s41467-025-60746-w}
}
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.
Key findings
- In the APPswe/PS1dE9 (APP/PS1) mouse model of amyloidosis, we demonstrated that microglial Cx43 hemichannels correlated with microglial malfunction, which in turn exacerbated β-amyloid pathology.
Why it matters
In a mouse model of amyloidosis, blocking microglial connexin43 hemichannels, either by genetic knockout or with a nanoparticle-delivered peptide, shifted microglia to a neuroprotective state and reduced amyloid-related pathology and cognitive impairment. These are animal results, and the authors call for advancing this approach into clinical trials rather than claiming it works in patients.
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 and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Communications) |
| Journal's citation record | 4 / 4 | Nature Communications: journal h-index 747 (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 “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 20 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 6.1× 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 | 2 / 4 | Cited 20 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Chenju Yi: h-index 28 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Manchester: institution h-index 1,304 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 4 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40595567) |
| Free to read | 2 / 2 | Free to read |
| Total | 48 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41467-025-60746-w
- PubMed: 40595567
- Original source →
- Free full text: Nature Communications →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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