Extending the functional characteristics of naturally occurring autoantibodies against β-Amyloid, Prion Protein and α-Synuclein

Background Abnormal aggregation of proteins induces neuronal cell loss in neurodegenerative disorders such as Alzheimer's Disease, Creutzfeldt-Jakob Disease and Parkinson's Disease. Specific stimuli initialize conformational changes in physiological proteins, causing intra- or extracellular protein aggregation. We and other groups have identified naturally occurring autoantibodies (nAbs) as part of the human antibody pool that are able to prevent peptide fibrillation. These nAbs show a rescue effect following exposure of toxic aggregates on neurons, and they support microglial uptake of aggregated peptides. Objective Identification of a putative common epitope among the relevant proteins beta-Amyloid, alpha-Synuclein and Prion Protein for the respective nAbs. Material and methods Binding affinity between the aforementioned proteins and nAbs was tested by Dot Blot, ELISA and SPR-technology. Furthermore, the functionality of the protein-nAbs-complexes was studied in Thioflavin-T assays and microglial uptake experiments to study dependent inhibition of protein aggregation and enhancement of Fc gamma mediated uptake by microglial cells. Results beta-Amyloid and Prion Protein fragment showed considerable binding affinity and functional efficacy for all applied nAbs. Thereby, no significant difference within the different nAbs was detected. In contrast, alpha-Synuclein was bound exclusively by nAbs-alpha-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with alpha-Synuclein revealed no significant effect of nAbs in comparison to IVIg treatment. However, all applied nAbs as well as IVIg show a minimal functionality on the microglial uptake of alpha-Synuclein. Conclusion nAbs-A beta, nAbs-PrP possibly display comparable affinity to the same structural epitope within A beta and PrP106-126 A117V whereas the epitope recognized by nAbs-alpha-Syn is only present in alpha-Syn. The structural similarity of A beta and PrP fragment promotes the outline for an efficient antibody for the treatment of several neurodegenerative disorders and extend the functional characteristics of the investigated nAbs.