A single domain antibody targeting Tau nucleation core inhibits Tau seeding

Authors

Clément Danis¹ , Elian Dupré¹ , Orgeta Zejneli² , Raphaëlle Caillierez² , Alexis Arrial³ , Séverine Bégard² , Anne Loyens² , Justine Mortelecque¹ , François-Xavier Cantrelle¹ , Xavier Hanoulle¹ , Jean-Christophe Rain⁴ , Morvane Colin² , Luc Buée² , Isabelle Landrieu¹

1. CNRS EMR9002 BSI Integrative Structural Biology, Lille, France
2. Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, Fr
3. Hybrigenics services, Evry-Courcouronnes, France
4. Hybrigenics Services, Evry-Courcouronnes, France

Conference / event

EuroTau meeting, November 2021 (Lille, France)

Poster summary

Tau proteins aggregate into filaments in brain cells in Alzheimer’s disease and related disorders named tauopathies. We used fragments of camelid heavy-chain-only antibodies (VHHs or single domain antibody fragments) targeting Tau as immuno-modulators of its pathologic seeding. A VHH issued from the screen against Tau of a synthetic phage-display library of humanized VHHs was selected for its capacity to bind Tau microtubule-binding domain, composing the core of Tau fibrils. This VHH, named Z70, was efficient in inhibiting in vitro Tau fibrils assembly in heparin-induced assays. Expression of VHH Z70 in a cellular model of Tau seeding also decreased the fluorescence-reported signal. Finally, intracellular expression of VHH Z70 in the brain of an established tauopathy mouse seeding model demonstrated its capacity to mitigate accumulation of pathological Tau. VHH Z70, by targeting Tau inside brain neurons, provides a tool to explore the optimal strategies of immunotherapy in tauopathies.

Keywords

Nanobodies, Tau protein, Protein aggregation, Tauopathies, Tau fibrils, Immunotherapy

Research areas

Biological Sciences, Biochemistry, Neuroscience

References

1. Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment. Danis C, Dupré E, Zejneli O, Caillierez R, Arrial A, Bégard S, Mortelecque J, Eddarkaoui S, Loyens A, Cantrelle FX, Hanoulle X, Rain JC, Colin M, Buée L, Landrieu I. Mol Ther. 2022 Apr 6;30(4):1484-1499. doi: 10.1016/j.ymthe.2022.01.009
2. https://www.wwpdb.org/ with access code 7QCQ

Funding

1. Agence nationale de la recherche ANR (No. ANR-11-LABX-01)
2. Agence nationale de la recherche ANR (No. ANR-18-CE44-0016)
3. European Union (No. Grant Agreement N° 305299)

Supplemental files

No data provided

Additional information

Competing interests

No competing interests were disclosed.

Data availability statement

The datasets generated during and / or analyzed during the current study are available from the corresponding author on reasonable request.

Creative Commons license

Copyright © 2023 Danis et al. This is an open access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.