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

Nature communications 2025

["Danis C", "Dupr\u00e9 E", "Bouillet T", "Den\u00e9chaud M", "Lefebvre C", "Nguyen M", "Mortelecque J", "Cantrelle F", "Rain J", "Hanoulle X"]

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.

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