Inhibition of tau neuronal internalization using anti-tau single domain antibodies

Clément Danis (), Elian Dupré, Thomas Bouillet, Marine Denéchaud, Camille Lefebvre, Marine Nguyen, Justine Mortelecque, François-Xavier Cantrelle, Jean-Christophe Rain, Xavier Hanoulle, Morvane Colin, Luc Buée () and Isabelle Landrieu ()
Additional contact information
Clément Danis: CNRS EMR9002 – BSI - Integrative Structural Biology
Elian Dupré: CNRS EMR9002 – BSI - Integrative Structural Biology
Thomas Bouillet: U1172 - LilNCog - Lille Neuroscience & Cognition
Marine Denéchaud: U1172 - LilNCog - Lille Neuroscience & Cognition
Camille Lefebvre: U1172 - LilNCog - Lille Neuroscience & Cognition
Marine Nguyen: CNRS EMR9002 – BSI - Integrative Structural Biology
Justine Mortelecque: CNRS EMR9002 – BSI - Integrative Structural Biology
François-Xavier Cantrelle: CNRS EMR9002 – BSI - Integrative Structural Biology
Jean-Christophe Rain: Hybrigenic Services
Xavier Hanoulle: CNRS EMR9002 – BSI - Integrative Structural Biology
Morvane Colin: U1172 - LilNCog - Lille Neuroscience & Cognition
Luc Buée: U1172 - LilNCog - Lille Neuroscience & Cognition
Isabelle Landrieu: CNRS EMR9002 – BSI - Integrative Structural Biology

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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 Z70mut1. These VHHs compete with the membrane protein LRP1, a major receptor mediating neuronal uptake of tau. A31 and Z70mut1 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.

Date: 2025
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DOI: 10.1038/s41467-025-58383-4

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