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RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease
Miao-Jin Ji, Yun Li, Jiao Yang, Kangjunjie Wang, Shuning Sang, Hong Yang, Chenhao Tian, Xin Tang et al.. Acta neuropathologica communications, 2025-09-24
Topic: Disease mechanisms in lab and animal studies
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder among the elderly, with limited effective treatments available in clinical practice. Impaired glucose metabolism has long been observed in the brains of AD patients, yet the mechanisms linking metabolic signals to AD pathogenesis remain elusive. Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation. Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD. Genetic dephosphorylation of RNF168 S60 enhances DNA damage response, reduces double-strand breaks (DSBs), and ameliorates learning and memory deficits in Aβ-based mouse models of AD. Mechanistically, RNF168 S60 phosphorylation impairs long-term potentiation (LTP) of mossy fiber-CA3 synapses in the hippocampus. Importantly, genetic dephosphorylation of RNF168 S60 rescues the deficits in Mossy fiber-CA3 synapse LTP, AD-related spine loss and Aβ pathology. Pharmacological inhibition of RNF168 phosphorylation by S6K1 inhibitor PF-4,708,671 alleviated learning and memory deficits. Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation. Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer's disease.
Key findings
- Our previous study demonstrated that growth signals regulate genomic stability through RNF168 phosphorylation.
- Here, we report that phosphorylation of RNF168 at Ser60 is significantly elevated in the hippocampi of Aβ-based mouse models of AD.
- Furthermore, we demonstrated that the anti-hyperglycemia drug metformin improved learning and memory by inhibiting RNF168 phosphorylation.
- Our findings provide a novel therapeutic target for addressing synaptic dysfunction in Alzheimer's disease.
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 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 (Acta neuropathologica communications) |
| 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 | 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 | — / 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 40993809) |
| 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 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Ji, M.-J., Li, Y., Yang, J., Wang, K., Sang, S., Yang, H., et al. (2025). RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease. Acta neuropathologica communications. https://doi.org/10.1186/s40478-025-02115-8
Vancouver
Ji M.-J, Li Y, Yang J, Wang K, Sang S, Yang H, et al. RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease. Acta neuropathologica communications. 2025. doi:10.1186/s40478-025-02115-8. PMID: 40993809.
BibTeX
@article{ji2025-40993809,
author = {Ji, Miao-Jin and Li, Yun and Yang, Jiao and Wang, Kangjunjie and Sang, Shuning and Yang, Hong and Tian, Chenhao and Tang, Xin and others},
title = {{RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease}},
journal = {Acta neuropathologica communications},
year = {2025},
doi = {10.1186/s40478-025-02115-8},
pmid = {40993809},
url = {https://doi.org/10.1186/s40478-025-02115-8}
}
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