Clue for Development of Treatment of Alzheimer’s Disease

Successful 1,000-fold enhancement of reaction velocity constants for proteins’ change into toxic substances.

Researchers at Osaka University succeeded in increasing the velocity constant for a reaction in which proteins causing Alzheimer disease (AD) turn into toxic substances to 1,000 times by using optimum frequency of ultrasonic irradiation.

When an ultrasonic wave is irradiated in solution with proteins, cavitation bubbles often repeatedly grow and collapse. The group found that these bubbles collect harmless proteins in solution, generating toxic substances whenever they collapse, changing into aggregates. The group also found that this phenomenon became prominent at the frequency of about 30 kHz.

It is thought Amyloid-β peptides form neurotoxic aggregates in the brain, developing AD. In developing drugs, it’s important to identify and create toxic aggregates and explore drug candidates targeting them, but formation of Aβ aggregates often takes a very long time. Therefore, technology for accelerating the aggregation reaction in low concentrations has been greatly sought after.

Accelerating the aggregation reaction of Amyloid-β is also important in giving a diagnosis. For early detection of AD, it’s effective to evaluate the aggregation capacity of Amyloid-β. Individuals who have an internal environment in which Amyloid-β tends to aggregate have a high risk of developing AD. However, it’s difficult to aggregate Amyloid-β in the body, so technology for accelerating the aggregation reaction is required.

In recent years, it was found that ultrasonic irradiation increases the aggregation reaction of various proteins. Using their own ultrasonic irradiation device, this group explored conditions for enhancing aggregation of Amyloid-β by changing acoustic pressure and frequency in solution independently and accurately.

Image shows an aggregation acceleration model focused on cavitation-bubble dynamics.
This is an aggregation acceleration model focused on cavitation-bubble dynamics. Credit: Osaka University.

As a result, the group succeeded in increasing the reaction velocity constant to 1,000 times by optimizing acoustic pressure at a frequency of 30 kHz.

Furthermore, the group found out that this acceleration phenomenon was brought on by cavitation bubbles which generate and collapse along with the cycle of ultrasonic waves and succeeded in theoretically reproducing this phenomenon.

The group’s achievement can be applied to techniques for early diagnosis of AD and demonstrates the conditions for reducing various risks associated with diagnosis and treatment using ultrasonic waves.

About this neurology research

Funding: This research was supported by The Cabinet Office, Government of Japan.

Source: Saori Obayashi – Osaka University
Image Source: The image is credited to Osaka University.
Original Research: Full open access research for “Nucleus factory on cavitation bubble for amyloid β fibril” by Kichitaro Nakajima, Hirotsugu Ogi, Kanta Adachi, Kentaro Noi, Masahiko Hirao, Hisashi Yagi and Yuji Goto in Scientific Reports. Published online February 25 2016 doi:10.1038/srep22015


Abstract

Nucleus factory on cavitation bubble for amyloid β fibril

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.

“Nucleus factory on cavitation bubble for amyloid β fibril” by Kichitaro Nakajima, Hirotsugu Ogi, Kanta Adachi, Kentaro Noi, Masahiko Hirao, Hisashi Yagi and Yuji Goto in Scientific Reports. Published online February 25 2016 doi:10.1038/srep22015

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