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Conformation-based detection of tau seeds with a novel VHH
GUPTA A, Liu R, Keely D, Sunderman V, Tak Y, Konstantoulea K, Terpack S, White CL et al.. Research Square, 2025-12-08
Topic: Disease mechanisms in lab and animal studies
In Alzheimer’s disease (AD) and related tauopathies, progressive pathology has been linked to prion mechanisms whereby ordered tau assemblies, or “seeds,” form in one cell and transit to neighboring or connected cells where they serve as templates for their own replication. While post-translational modifications of pathological tau have been useful to mark pathology, effective methods to accurately detect and target pathogenic seed conformations remain limited. We report a novel discovery and characterization paradigm to identify camelid variable heavy domain of heavy chain (VHH) sequences with desired properties. From a published synthetic VHH yeast display library, we screened for clones capable of immunoprecipitating tau seeds from human tauopathy brain homogenates and identified two seed-selective anti-tau VHHs – VHH(510) and VHH(50) – that target pathological tau. These VHHs preferentially target tau seeds present in AD, corticobasal degeneration (CBD), and PS19 tauopathy mouse brains. We enhanced their stability through framework mutations (M), while maintaining their seed-binding characteristics. We characterized VHH(510M) in detail, determining that it bound the carboxy terminus of tau with robust avidity for seeds, and low affinity for monomer. When used to stain mouse and human brain tissues, VHH(510M) revealed pathological tau accumulation that was often independent of AT8-positive lesions. The distinct staining pattern observed with anti-tau VHH(510M) underscores the potential of VHH-based reagents for PET imaging and histopathology. Adaptation of VHH(510M) could also improve therapy and diagnosis for diverse tauopathies.
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APA 7th
GUPTA, A., Liu, R., Keely, D., Sunderman, V., Tak, Y., Konstantoulea, K., et al. (2025). Conformation-based detection of tau seeds with a novel VHH. Research Square. https://doi.org/10.21203/rs.3.rs-8274351/v1
Vancouver
GUPTA A, Liu R, Keely D, Sunderman V, Tak Y, Konstantoulea K, et al. Conformation-based detection of tau seeds with a novel VHH. Research Square. 2025. doi:10.21203/rs.3.rs-8274351/v1.
BibTeX
@article{gupta2025-20b76129,
author = {GUPTA, A. and Liu, R. and Keely, D. and Sunderman, V. and Tak, Y. and Konstantoulea, K. and Terpack, S. and White, C. L. and others},
title = {{Conformation-based detection of tau seeds with a novel VHH}},
journal = {Research Square},
year = {2025},
doi = {10.21203/rs.3.rs-8274351/v1},
url = {https://doi.org/10.21203/rs.3.rs-8274351/v1}
}
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Key findings
- When used to stain mouse and human brain tissues, VHH(510M) revealed pathological tau accumulation that was often independent of AT8-positive lesions.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 19 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. 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 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 and multi-centre collaboration, so those were left out: it earned 12 of the 62 points we could judge it on, which is 19 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 12 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 12 of the 62 points we could judge it on is 19 out of 100. |
| Total | 19 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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