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Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region
Tomas Ondrejcak, Neng-Wei Hu, Emily Coode, Tom Campbell, Grant T Corbett, Ivan Doykov, Kevin Mills, Dominic M Walsh et al.. Acta neuropathologica, 2025-06-02
Topic: Disease mechanisms in lab and animal studies
Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimer's disease (AD) will slow dementia pathogenesis. Whether these interventions affect the actions of synaptotoxic, extracellular tau species that may contribute to cognitive impairment is relatively unknown. Here, we assayed synaptic plasticity disruption in anaesthetised live rats caused by intracerebral injection of synaptotoxic tau present either in (a) secretomes of induced pluripotent stem cell-derived neurons (iNs) from people with Trisomy 21, the most common genetic cause of AD, or (b) aqueous extracts of human AD brain. Extracellular tau in iN secretomes was found to include fragments that contain the extended microtubule-binding regions of tau, MTBR/R' and adjacent C-terminal sequences. Immunodepletion or co-injection with antibodies targeting epitopes within these fragments prevented the acute disruption of synaptic plasticity by these patient-derived synaptotoxic tau preparations. Moreover, a recombinant human tau fragment encompassing the core MTBR/R'-region present in tau fibrils, tau297-391, potently mimicked the deleterious action of patient-derived tau. MTBR/R'-directed antibodies also rapidly reversed a very persistent synaptotoxic effect of soluble brain tau. Our findings reveal a hitherto relatively unexplored potential benefit of targeting extracellular MTBR/R' tau on correcting synaptic dysfunction.
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APA 7th
Ondrejcak, T., Hu, N.-W., Coode, E., Campbell, T., Corbett, G. T., Doykov, I., et al. (2025). Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region. Acta neuropathologica. https://doi.org/10.1007/s00401-025-02897-0
Vancouver
Ondrejcak T, Hu N.-W, Coode E, Campbell T, Corbett GT, Doykov I, et al. Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region. Acta neuropathologica. 2025. doi:10.1007/s00401-025-02897-0. PMID: 40455293.
BibTeX
@article{ondrejcak2025-40455293,
author = {Ondrejcak, Tomas and Hu, Neng-Wei and Coode, Emily and Campbell, Tom and Corbett, Grant T and Doykov, Ivan and Mills, Kevin and Walsh, Dominic M and others},
title = {{Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region}},
journal = {Acta neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02897-0},
pmid = {40455293},
url = {https://doi.org/10.1007/s00401-025-02897-0}
}
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Key findings
- Our findings reveal a hitherto relatively unexplored potential benefit of targeting extracellular MTBR/R' tau on correcting synaptic dysfunction.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty 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 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| 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 40455293) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
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