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A phenotypic screen for novel small molecules that correct tau‐mediated pathologies in human frontotemporal dementia neurons
Hannah Maxwell, James C. Smith, Tom A. Campbell, Jason Clark, Rosanna La Rocca, Francesco Paonessa, Sergey Sitnikov, Mark L. Evans et al.. Alzheimer s & Dementia, 2025-09-01
Topic: Brain proteins, microglia and lab models
Screening a 19,786-compound chemical diversity library, we identified > 100 compounds that corrected nuclear membrane defects in MAPT IVS10+16 neurons, with 23 demonstrating robust dose-dependent rescue. A common feature of hit compounds was alteration of the neuronal microtubule cytoskeleton, with a subset changing neuronal tau protein levels or phosphorylation. Human models of tauopathy were used in a phenotypic screen to identify novel chemotypes that correct a validated pathology, illustrating the value of human models of neurodegenerative disease in the drug discovery process. HIGHLIGHTS: A phenotypic screen for novel small molecules that suppress tau-mediated pathologies was carried out in human frontotemporal dementia neurons. The key readout was correction of nuclear membrane defects, which are a pathological feature in tauopathies in vivo. The screen of 20,000 small molecules identified more than 20 compounds that corrected the phenotype in a dose-dependent manner. Hit compounds commonly altered microtubules, with a subset changing tau protein levels or phosphorylation.
Key findings
- Screening a 19,786-compound chemical diversity library, we identified > 100 compounds that corrected nuclear membrane defects in MAPT IVS10+16 neurons, with 23 demonstrating robust dose-dependent rescue.
- A common feature of hit compounds was alteration of the neuronal microtubule cytoskeleton, with a subset changing neuronal tau protein levels or phosphorylation.
- Human models of tauopathy were used in a phenotypic screen to identify novel chemotypes that correct a validated pathology, illustrating the value of human models of neurodegenerative disease in the drug discovery process.
- HIGHLIGHTS: A phenotypic screen for novel small molecules that suppress tau-mediated pathologies was carried out in human frontotemporal dementia neurons.
- The key readout was correction of nuclear membrane defects, which are a pathological feature in tauopathies in vivo.
Why it matters
In a screen of 19,786 compounds using human frontotemporal dementia neurons, more than 100 compounds corrected nuclear membrane defects and 23 showed robust dose-dependent rescue, with many hits altering microtubules and some changing tau levels or phosphorylation. This is a laboratory drug-discovery screen, so no treatment for patients is established.
Study details
- Evidence strengthLow
How this study scored 34/100
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 (Alzheimer s & Dementia) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (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 3 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.6× 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 | 1 / 4 | Cited 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Rick Livesey: h-index 6 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Takeda (Japan): institution h-index 377 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40891380) |
| Free to read | 2 / 2 | Free to read |
| Total | 34 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Maxwell, H., Smith, J. C., Campbell, T. A., Clark, J., La Rocca, R., Paonessa, F., et al. (2025). A phenotypic screen for novel small molecules that correct tau‐mediated pathologies in human frontotemporal dementia neurons. Alzheimer s & Dementia. https://doi.org/10.1002/alz.70620
Vancouver
Maxwell H, Smith JC, Campbell TA, Clark J, La Rocca R, Paonessa F, et al. A phenotypic screen for novel small molecules that correct tau‐mediated pathologies in human frontotemporal dementia neurons. Alzheimer s & Dementia. 2025. doi:10.1002/alz.70620. PMID: 40891380.
BibTeX
@article{maxwell2025-40891380,
author = {Maxwell, Hannah and Smith, James C. and Campbell, Tom A. and Clark, Jason and La Rocca, Rosanna and Paonessa, Francesco and Sitnikov, Sergey and Evans, Mark L. and others},
title = {{A phenotypic screen for novel small molecules that correct tau‐mediated pathologies in human frontotemporal dementia neurons}},
journal = {Alzheimer s \& Dementia},
year = {2025},
doi = {10.1002/alz.70620},
pmid = {40891380},
url = {https://doi.org/10.1002/alz.70620}
}
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