Beta Amyloid Oligomers with Higher Cytotoxicity have Higher Sidechain Dynamics

The underlying biophysical principle governing the cytotoxicity of the oligomeric aggregates of beta-amyloid (A beta) peptides has long been an enigma. Here we show that the size of A beta(40) oligomers can be actively controlled by incubating the peptides in reverse micelles. Our approach allowed for the first time a detailed comparison of the structures and dynamics of two A beta(40) oligomers of different sizes, viz., 10 and 23 nm, by solid-state NMR. From the chemical shift data, we infer that the conformation and/or the chemical environments of the residues from K16 to K28 are different between the 10-nm and 23-nm oligomers. We find that the 10-nm oligomers are more cytotoxic, and the molecular motion of the sidechain of its charged residue K16 is more dynamic. Interestingly, the residue A21 exhibits unusually high structural rigidity. Our data raise an interesting possibility that the cytotoxicity of A beta(40) oligomers could also be correlated to the motional dynamics of the sidechains.

Automated summary

In this study, the structures and dynamics of A beta(40) oligomers of different sizes (10 nm and 23 nm) were compared for the first time using solid-state NMR. Chemical shift data suggest that the conformation and/or chemical environments of residues from K16 to K28 differ between the 10-nm and 23-nm oligomers. The 10-nm oligomers were found to be more cytotoxic, with more dynamic molecular motion of the sidechain of its charged residue K16. Interestingly, residue A21 exhibited unusually high structural rigidity. These findings raise the intriguing possibility that the cytotoxicity of A beta(40) oligomers could be correlated to the motional dynamics of the sidechains.