Expression and characterization of an Aβ oligomer binding single-chain variable fragment – a novel tool for the treatment of Alzheimer’s disease?

Alzheimer's disease is a progressive neurodegenerative disorder with devastating effects. Currently, only palliative therapies are available. In recent years, Aβ immunotherapy has become a promising tool for the treatment of AD. Both, entire antibodies as well as antibody fragments have been shown to reduce amyloid-β (Aβ) plaque burden and ameliorate cognitive deficits in AD mouse models. However, clinical trials with active immunization using Aβ encountered severe complications, for example meningoencephalitis. Alternatively, single-chain variable fragments (scFvs) can be used in therapeutic approaches. These were shown to alter Aβ aggregation and toxicity.

In this study, we selected an IgG using the N-terminal region of Aβ in the selection procedure. The corresponding scFv was expressed in E. coli, purified and characterized regarding its interaction with different Aβ species and its influence on Aβ fibril formation. We were able to show that the identified scFv strongly influenced the aggregation behavior of Aβ. Moreover, it also bound to Aβ oligomers and fibrils with higher affinity than to Aβ monomers. Docking experiments suggest that the scFv binds to His14 und Lys16 of the N-terminal pile of Aβ fibrils.

Because the identified scFv specifically targets higher oligomeric species of Aβ and prevents Aβ fibril formation, it would be a valuable candidate for therapeutic approaches.