Selective Targeting of Pathogenic Tau Seeds via a Novel VHH

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. Despite intensive efforts to develop early diagnosis and effective treatment, none has emerged. This is due partly to the structural heterogeneity of tau seeds and limitations in selectively targeting their pathogenic conformations. Here we report the discovery of a camelid variable heavy domain of heavy chain (VHH) that preferentially binds tau seeds of AD, corticobasal degeneration (CBD), and PS19 tauopathy mouse brains. From a published synthetic VHH yeast display library, we identified VHH clones that bound 2N4R tau monomer. After counter-screening for immunoprecipitation of seeding from human brain, we identified two seed-selective anti-tau VHH—VHH(510) and VHH(50)—that preferentially bound pathological tau. We enhanced the stability of these VHHs through framework mutations without affecting their seed-binding characteristics. We characterized VHH(510) in detail, determining that it binds the carboxy terminus of tau, maintains robust seed avidity even in the presence of competing monomer, and stains pathological tau inclusions in mouse and human AD tissues. These results highlight the power of seed-selective VHH to bind pathogenic tau, paving the way for future therapeutic and diagnostic applications across a wide range of neurodegenerative disorders.