FF Activates Nucleation for Aggregation in Aqueous Medium: A Key Insight of Amyloid Plaque Formation

Abstract

AbstractMolecular self‐association of monomers with multifaceted cross‐linkers, opens new possibilities for the development of various supramolecular‐networks that enable to participate in different functions. Plaques associated with senility that form in the brains of Alzheimer′s patients are mainly composed of beta amyloid (Aβ). It can be assumed that there must be a nucleation site which through reverse folding initiate to aggregate this Aβ plaque. It has been reported KLVFFA motif of Aβ sequence plays an important role as the amylogenic unit for Alzheimer disease. In order to identify the shortest sequence that would initiate the nucleation for such aggregation, we have synthesized N‐terminal protected two two‐residue peptides [Hex‐Phe(1)‐Phe(2)‐OMe: (FF)] and [Hex‐Phe(1)‐Ala(2)‐OMe: (FA)] an important fragment of KLVFFA motif. Using various microscopic and biophysical approaches, including measuring the hydrodynamic radii, it is observed that in fully aqueous condition in comparison to FA, FF nucleates higher degree of aggregates, along with substantial formation of dendrimeric amyloid fibrils, which has been elegantly visualized in Congo‐red assay through formation of distinct apple‐green birefringence. Such an observation leads to hypothesize that the ‘di‐phenylalanine’ unit (FF) plays a crucial role as the nucleation site towards attaining the aggregate for formation of the Aβ plaque through reverse folding.