Abstract
Structural evolution from monomer to fibril of amyloid β peptide is related to pathogenic mechanism of Alzheimer disease, and its acceleration is a long-running problem in drug development. This study reveals that ultrasonic cavitation bubbles behave as catalysts for nucleation of the peptide: The nucleation reaction is highly dependent on frequency and pressure of acoustic wave, and we discover an optimum acoustical condition, at which the reaction-rate constant for nucleation is increased by three-orders-of magnitudes. A theoretical model is proposed for explaining highly frequency and pressure dependent nucleation reaction, where monomers are captured on the bubble surface during its growth and highly condensed by subsequent bubble collapse, so that they are transiently exposed to high temperatures. Thus, the dual effects of local condensation and local heating contribute to dramatically enhance the nucleation reaction. Our model consistently reproduces the frequency and pressure dependences, supporting its essential applicability.
Highlights
Structural evolution from monomer to fibril of amyloid β peptide is related to pathogenic mechanism of Alzheimer disease, and its acceleration is a long-running problem in drug development
To reproduce these experimental results theoretically, we propose an aggregation acceleration model based on the dual effects of local condensation and local heating accompanied with the bubble collapse: Aβ monomers will be adsorbed on the bubble surface during bubble growth because of the presence of hydrophobic residues, they are condensed when the bubble shrinks for collapse, and they are exposed to extremely high temperature field near the hot spot at the bubble collapse
Because ThT molecules bind to the cross-β-sheet structure, which is unit structure of Aβ fibril, and cause emission, the ThT assay has been widely adopted for monitoring the aggregation reaction of Aβ peptides[32,33]
Summary
Structural evolution from monomer to fibril of amyloid β peptide is related to pathogenic mechanism of Alzheimer disease, and its acceleration is a long-running problem in drug development. Because the hot-spot temperature is highly affected by frequency and pressure of the driving acoustic wave[31], we investigate ultrasonically accelerated aggregation behavior with various frequencies and pressures systematically in order to clarify its mechanism, which has not been done because of difficulty of controlling the acoustic field inside sample tubes.
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