Construction of a DNA Nanoassembly Based on Spatially Ordered Recognition Elements for Inhibiting beta-Amyloid Aggregation

A P'-amyloid (AP') aggregation process is a spontaneous process where the original random coil or helical structure changes into a regularly arranged P'-sheet structure. The development of inhibitors with the features of low cost, high efficiency, and biosafety by targeting AP' self-aggregation is significant for Alzheimer's disease treatment. However, the issues of low inhibition efficiency under low concentrations of inhibitors and biological toxicity are currently to be addressed. To resolve the above problems, a DNA nanoassembly (HCR-Apt) based on spatially ordered recognition elements was constructed by targeted disruption of AP' ordered arrangement. It was discovered that HCR-Apt could inhibit effectively the fibrillation of AP'40 monomers and oligomers at substoichiometric ratios. This may be due to orderly arrangement of aptamers in rigid nanoskeletons for enhancing the recognition interaction between aptamers and AP'40. The strong interaction between HCR-Apt and AP'40 limited the flexible conformational conversion of AP'40 molecules, thereby inhibiting their self-assembly. Computational simulations and experimental analysis revealed the interactions of Apt42 with AP'40, which explained different inhibition effects on the fibrillation of AP'40 monomers and oligomers. Furthermore, the analysis of tyrosine intrinsic fluorescence spectra and surface plasmon resonance imaging showed that the interaction of HCR-Apt and AP'40 was stronger than that of Apt42 and AP'40. These findings contributed to establishing a promising method of boosting the recognition interaction by orderly arrangement of recognition elements. Taken together, this work is expected to provide a simple and efficient strategy for inhibiting AP' aggregation, expanding aptamer's application potential in neurodegenerative diseases.