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Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice
Yixiang Jiang, Amber M. Tetlow, Yan Lin, Changyi Ji, Jack Ader, Klaudia Flóra Laborc, Adam C. Mar, Ruimin Pan et al.. Science Translational Medicine, 2026-04-15
Topic: Brain proteins, microglia and lab models
Tauopathies are neurodegenerative diseases characterized by pathological tau accumulation, leading to motor and neuropsychiatric symptoms. Effective tau-targeting therapies remain a major challenge, in part because tau lacks well-defined druggable sites and accumulates as heterogeneous intracellular aggregates that are difficult to access and clear. Here, we present 1D9-LIRΔTP53INP2, a single-domain antibody (sdAb)-based protein degrader that facilitates tau clearance through the autophagy-lysosomal pathway. This engineered molecule combines the anti-tau sdAb 1D9 with an LC3-interacting region (LIRΔTP53INP2) to promote autophagosomal recruitment, mimicking autophagy receptors by simultaneously binding tau and LC3. In neurons derived from patients with frontotemporal dementia (FTD) and JNPL3 tauopathy mice, both harboring the P301L tau mutation, 1D9-LIRΔTP53INP2 promoted autophagy-lysosome-mediated tau degradation. It readily crossed the blood-brain barrier and improved motor function in JNPL3 tauopathy mice. These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies. Given the challenges of brain delivery for conventional antibodies, sdAbs with enhanced brain penetration and efficacy offer a promising strategy for treatment of neurodegenerative diseases.
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APA 7th
Jiang, Y., Tetlow, A. M., Lin, Y., Ji, C., Ader, J., Laborc, K. F., et al. (2026). Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aea4205
Vancouver
Jiang Y, Tetlow AM, Lin Y, Ji C, Ader J, Laborc KF, et al. Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice. Science Translational Medicine. 2026. doi:10.1126/scitranslmed.aea4205. PMID: 41984931.
BibTeX
@article{jiang2026-41984931,
author = {Jiang, Yixiang and Tetlow, Amber M. and Lin, Yan and Ji, Changyi and Ader, Jack and Laborc, Klaudia Flóra and Mar, Adam C. and Pan, Ruimin and others},
title = {{Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice}},
journal = {Science Translational Medicine},
year = {2026},
doi = {10.1126/scitranslmed.aea4205},
pmid = {41984931},
url = {https://doi.org/10.1126/scitranslmed.aea4205}
}
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Key findings
- These findings underscore the therapeutic potential of sdAb-based protein degraders for tauopathies.
Why it matters
An engineered single-domain antibody cleared tau through the autophagy-lysosomal pathway in neurons from patients with frontotemporal dementia and in JNPL3 tauopathy mice, and improved motor function in the mice. This is cell and animal work, so it does not yet show a treatment for people.
Study details
- Evidence strengthLow
How this study scored 36/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science Translational Medicine) |
| Journal's citation record | 3 / 4 | Science Translational Medicine: journal h-index 365 (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 | 5 / 5 | 2026 — within 1 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 “mice”) — scores zero |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.5 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 3 / 6 | Cited 4.2× 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 | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Einar M. Sigurdsson: h-index 49 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | New York University: institution h-index 1,612 (OpenAlex) |
| Multicenter 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 41984931) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 36 / 100 | — |
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