Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers

Abstract

Abstract Alzheimer’s disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Immunotherapy targeting and resolving the pathological tau aggregates is known to improve cognitive deficits in AD animal models. The repeat domain of tau (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Considering that TauRD forms the structural core of tau aggregates, the development of immunotherapy selectively targeting TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated a recombinant TauRD polypeptide forming neurofibrillary tangle (NFT)-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum could also specifically recognize pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested the vaccine efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, such as memory deficits, and ameliorated tauopathy progression. More notably, the survival of the vaccinated mice was dramatically extended. Conclusively, we have developed a mucosal vaccine exclusively targeting pathological tau conformers and preventing disease progression.