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Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease
Kevin Fang, Ehsan Pishva, Thomas Piers, Steffen Scholpp. Journal of cell science, 2025-02-05
Topic: Disease mechanisms in lab and animal studies
Wnt signalling is an essential signalling system in neurogenesis, with a crucial role in synaptic plasticity and neuronal survival, processes that are disrupted in Alzheimer's disease (AD). Within this network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical Wnt-planar cell polarity (Wnt/PCP) pathway in AD remains to be determined. This study investigates the role of ROR2, a Wnt/PCP co-receptor, in synaptogenesis. We demonstrate that WNT5A-ROR2 signalling activates the JNK pathway, leading to synapse loss in mature neurons. This effect mirrors the synaptotoxic actions of Aβ1-42 and DKK1, which are elevated in AD. Notably, blocking ROR2 and JNK mitigates Aβ1-42 and DKK1-induced synapse loss, suggesting their dependence on ROR2. In induced pluripotent stem cell (iPSC)-derived cortical neurons carrying a PSEN1 mutation, known to increase the Aβ42/40 ratio, we observed increased WNT5A-ROR2 clustering and reduced numbers of synapses. Inhibiting ROR2 or JNK partially rescued synaptogenesis in these neurons. These findings suggest that, unlike the Wnt/β-catenin pathway, the Wnt/PCP-ROR2 signalling pathway can operate in a feedback loop with Aβ1-42 to enhance JNK signalling and contribute to synapse loss in AD.
Key findings
- In induced pluripotent stem cell (iPSC)-derived cortical neurons carrying a PSEN1 mutation, known to increase the Aβ42/40 ratio, we observed increased WNT5A-ROR2 clustering and reduced numbers of synapses.
- These findings suggest that, unlike the Wnt/β-catenin pathway, the Wnt/PCP-ROR2 signalling pathway can operate in a feedback loop with Aβ1-42 to enhance JNK signalling and contribute to synapse loss in AD.
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Study details
- Evidence strengthLow
How this study scored 43/100
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 journal's citation record, 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, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of cell science) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | — / 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 | 2 / 2 | Indexed in PubMed (PMID 39907042) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Fang, K., Pishva, E., Piers, T., & Scholpp, S. (2025). Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease. Journal of cell science. https://doi.org/10.1242/jcs.263526
Vancouver
Fang K, Pishva E, Piers T, Scholpp S. Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease. Journal of cell science. 2025. doi:10.1242/jcs.263526. PMID: 39907042.
BibTeX
@article{fang2025-39907042,
author = {Fang, Kevin and Pishva, Ehsan and Piers, Thomas and Scholpp, Steffen},
title = {{Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease}},
journal = {Journal of cell science},
year = {2025},
doi = {10.1242/jcs.263526},
pmid = {39907042},
url = {https://doi.org/10.1242/jcs.263526}
}
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