Template-Mediated Detoxification of Low-Molecular-Weight Amyloid Oligomers and Regulation of Their Nucleation Pathway.

Amyloid tetramer, the most toxic low-molecular-weight (LMW) amyloid oligomer, leads to synaptic dysfunction and plays a vital role in pathophysiology of Alzheimer's disease (AD). Hence, their kinetic inhibition may be regarded as a potential therapeutic strategy against AD. However, because of their dynamic, metastable nature, not much information has been gathered about them. Herein, amyloid tetramers have been isolated from a mixture pool of low- and high-molecular-weight amyloid oligomers. Kinetics of such tetrameric species has been studied in an in vitro model and inhibition of the fibrillation of the species has been achieved by means of a novel isatin functionalized polyfluorene derivative (PFIS). Isatin interacts with tetramers noncovalently to modulate its fibrillation by forming stable polymer-peptide coaggregates. In parallel to this, hydrophobic PFIS forms spherical nanoparticle in water that provides an external surface, which functions to modulate nucleation pathway of the oligomers. The polymer-peptide coaggregates are nontoxic in nature. Hence, these observations offer a potential strategy to suppress neurotoxicity of a LMW oligomer by forming nontoxic coaggregates. In parallel to this, our methodology also provides a potential strategy to observe and regulate nucleation pathway of the oligomers as well.