Role of Surface Charge of Inhibitors on Amyloid Beta Fibrillation

Several kinds of small molecules and nanopartides (NP) are known for effective inhibition of amyloid fibrillation, which is known as a precursor for many neurodegenerative diseases. We address the role of the surface charge of NP in this process from a systematic study using charged NP and surfactants. The fibrillation kinetics is investigated using time-resolved Thioflavin T fluorescence and tansmission electron microscopy. It is found that if the protein residues corresponding to the beta-sheet (key secondary structure for the formation of fibrils) are charged, addition of oppositely charged NP will inhibit the fibrillation process, irrespective of the material composition of the NP. Molecular dynamics simulations show that electrostatic interaction between the beta-sheet forming residues and the NP is responsible for this effect. The finding is further validated by using oppositely charged surfactants: like-charged surfactants and NP do not affect the fibrillation kinetics. Further, even the preformed fibrils are dissociated into protein aggregates upon adding oppositely charged NP/surfactants. These results suggest that NP can be used as therapeutic agents even after the fibrils are formed and that they can be dissolved into soluble aggregates. The inhibitory effect is essentially decided by the charge of the inhibitor, irrespective of the size, shape, and material composition. The study provides new insight for the rational design of nanoparticle-based therapeutics, with appropriate surface charge, to inhibit the onset of arnyloid beta fibrillation and to dissociate the preformed fibrils.