Peptide-Polyphenol (KLVFF/EGCG) binary modulators for inhibiting aggregation and neurotoxicity of amyloid-β peptide

Abstract

Alzheimer's disease (AD) is known as a typical neurodegenerative disease, and the pathogenic hallmark is the aggregation and deposition of amyloid-β peptide (Aβ) fibrils and plaque on neuronal cells resulting in cell dysfunction and cell death. One effective approach to preventing and curing AD lies in tuning Aβ aggregation and inhibiting the neurotoxicity by using molecular modulators. Peptide breakers and antioxidants are widely used inhibitors to modulate Aβ aggregation and neurotoxicity, although less efficiency of single modulators hinders the practical application of these molecules. An integration of different molecular modulators is expected to make use of multiple interactions and modulating sites and therefore synergistically improve the capacity of modulators in inhibiting Aβ aggregation. In this work, the concept of a binary peptide-polyphenol binary modulator (Aβ-segment KLVFF and (A)-epigallocatechin-3-gallate, KLVFF/EGCG) is proposed, and the synergistic effect of the KLVFF/EGCG modulator is demonstrated for efficient inhibition of Aβ aggregation and neurotoxicity. With the aid of thioflavin T fluorescence, circular dichroism spectroscopy, atomic force microscopy, and transmission electron microscopy, the inhibitory effect on Aβ42 fibrillation was determined. Further liquid-state nuclear magnetic resonance spectroscopy and molecular dynamics simulations evidenced the affinity of the KLVFF/EGCG complex to the Aβ42 monomer. Furthermore, a tentative schematic mechanism is also proposed to illustrate the synergistic effect. Besides, the MTT assay and DCFH-DA (2′,7′-dichlorodihydrofluorescein diacetate) test were performed to explore the reduction of Aβ42-induced neurotoxicity by treating with the KLVFF/EGCG complex. The binary inhibitors showed remarkable reduction in Aβ42-induced ROS generation. This work could be beneficial for the designing of potential therapeutic binary modulators and shed light on AD prevention.