Abstract
BackgroundAbnormal 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.ObjectiveIdentification of a putative common epitope among the relevant proteins β-Amyloid, α-Synuclein and Prion Protein for the respective nAbs.Material and methodsBinding 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 Fcγ mediated uptake by microglial cells.Resultsβ-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, α-Synuclein was bound exclusively by nAbs-α-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with α-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 α-Synuclein.ConclusionnAbs-Aβ, nAbs-PrP possibly display comparable affinity to the same structural epitope within Aβ and PrP106-126 A117V whereas the epitope recognized by nAbs-α-Syn is only present in α-Syn. The structural similarity of Aβ 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.
Highlights
The structural similarity of Aβ 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 naturally occurring autoantibodies (nAbs)
The pathology of neurodegenerative disorders including Alzheimer’s Disease (AD), Creutzfeldt-Jakob Disease (CJD) and Parkinson’s Disease (PD) is characterized by a deposition of aggregated proteins in distinct areas within the brain, which causes destabilization of neuroplasticity followed by neuronal cell loss, resulting in specific clinical impairments [1]
All applied nAbs showed a binding to Aβ1–42 in Dot Blot (Fig 1A) as well as in ELISA (Fig 1B) and SPR (Fig 1C) experiments
Summary
The pathology of neurodegenerative disorders including Alzheimer’s Disease (AD), Creutzfeldt-Jakob Disease (CJD) and Parkinson’s Disease (PD) is characterized by a deposition of aggregated proteins in distinct areas within the brain, which causes destabilization of neuroplasticity followed by neuronal cell loss, resulting in specific clinical impairments [1]. CJD patients show extracellular PrPsc aggregates around neurons in affected brain areas These amyloid-like plaques are thought to induce neuronal dysfunction [6,7]. 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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
