Length-Dependent Distinct Cytotoxic Effect of Amyloid Fibrils beyond Optical Diffraction Limit Revealed by Nanoscopic Imaging

Fibrillar species have been proposed to play an essential role in the cytotoxicity of amyloid peptide and the pathogenesis of neurodegenerative diseases. Discrimination of Aβ aggregates in situ at high spatial resolution is therefore significant for the development of a therapeutic method. In this work, we adopt a rhodamine-like structure as luminescent centers to fabricate carbonized fluorescent nanoparticles (i.e., carbon dots, RhoCDs) with tunable emission wavelengths from green to red and burst-like photoblinking property for localization-based nanoscopic imaging. These RhoCDs contain lipophilic cationic and carboxyl groups which can specifically bind with Aβ1–40 aggregates via electrostatic interaction and hydrogen bonding. According to the nanoscopic imaging in the Aβ1–40 fibrillation and disaggregation process, different types of Aβ1–40 aggregates beyond the optical diffraction limit have been disclosed. Additionally, length-dependent toxic effect of Aβ1–40 aggregates beyond the optical diffraction limit is unveiled. Short amyloid assemblies with length of 187 ± 3.9 nm in the early stage are more toxic than the elongated amyloid fibrils. Second, disassembly of long fibrils into short species by Gramicidin S (GS-2) peptide might enhance the cytotoxicity. These results lay the foundation to develop functional fluorophore for nanoscopic imaging and also provide deep insight into morphology-dependent cytotoxicity from amyloid peptides.