Inhibition of tau neuronal internalization using anti-tau single domain antibodies
In Alzheimer's disease, tau pathology spreads across brain regions as the disease progresses. Intracellular tau can be released and taken up by nearby neurons. We evaluated single domain anti-tau antibodies, also called VHHs, as inhibitors of tau internalization. We identified three VHH inhibitors of tau uptake: A31, H3-2, and Z70<sub>mut1</sub>. These VHHs compete with the membrane protein LRP1, a major receptor mediating neuronal uptake of tau. A31 and Z70<sub>mut1</sub> bind to microtubule binding domain repeats, which are involved in the interaction with LRP1. VHH H3-2 is the only VHH from our library that reduces the internalization of both monomeric tau and tau fibrils. VHH H3-2 binds a C-terminal tau epitope with high affinity. Its three-dimensional structure in complex with a tau peptide reveals a unique binding mode as a VHH-swapped dimer. These anti-tau VHHs are interesting tools to study tau prion-like propagation in tauopathies and potentially develop novel biotherapies.
Authors
- Xavier Hanoulle (ORCID: https://orcid.org/0000-0002-3755-2680)
- Morvane Colin (ORCID: https://orcid.org/0000-0003-0611-4167)
- Jean‐Christophe Rain (ORCID: https://orcid.org/0000-0001-8110-0641)
- Justine Mortelecque (ORCID: https://orcid.org/0000-0001-6704-4495)
- Clément Danis (ORCID: https://orcid.org/0000-0002-5895-4742)
- Isabelle Landrieu (ORCID: https://orcid.org/0000-0002-4883-2637)
- Thomas Bouillet
- Elian Dupré (ORCID: https://orcid.org/0000-0001-5281-0337)
- Luc Buée (ORCID: https://orcid.org/0000-0002-6261-4230)
- François‐Xavier Cantrelle (ORCID: https://orcid.org/0000-0002-3413-5443)
- Camille Lefebvre (ORCID: https://orcid.org/0000-0002-1386-0611)
- Marine Denéchaud
- Marine Nguyen
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Hybrigenics (France) (FR)
- Lille Neurosciences & Cognition (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-02
- DOI
- https://doi.org/10.1038/s41467-025-58383-4
- Citations
- 13
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 15.14
Funders
- Alzheimer's Association
- Université de Lille
- European Commission
- Agence Nationale de la Recherche
- Association France Alzheimer
- Centre National de la Recherche Scientifique