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Examining the Mechanisms of Dementia-causing Amyloid-β Aggregate Formations

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  • Registration Date : 2019-08-06
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Examining the Mechanisms of Dementia-causing Amyloid-β Aggregate Formations

 

- Anticipating results leading to the development of innovative medications for treating diseases that cause amyloid-beta aggregation

- Results of joint research between the Republic of Korea (“ROK”), the United States of America (“USA”), and Japan published in the online edition of ACS Nano on July 16, 2019

 

 Recent studies have identified various mechanisms by which amyloid-beta peptides, proteins known to play a role in the onset of dementia, aggregate to create amyloid plaque which attacks neural cells. These results are expected to contribute not only to dementia research, but also to research on other diseases caused by protein aggregation.

* Amyloid plaque: spot-like masses that form in the brains of patients suffering from elderly dementia

 Dr. Lee Young-ho, a professor in the Department of Bio-Analytical Science at the University of Science and Technology, Korea (UST) and his team in the Division of Bioconvergence Analysis at the Korea Basic Science Institute (“KBSI”) collaborated as part of a joint ROK-USA-Japan research team examining the various formation mechanisms of Alzheimer’s amyloid-β (1-40).

 Generally amyloid-β is found throughout the cerebrospinal fluid in a string-like shape without any extraordinary structural characteristics. When these peptides begin to aggregate by connecting to each other side-by-side, they form fibrous structures known as amyloid fibrils which in turn create amyloid plaque. The research team discovered that various environmental factors, including fat and alcohol content, pH, and ionic strength, affect the structure and solubility of amyloid-β peptides, resulting in varying compositions of amyloid fibrils.

 An increase in the fat or alcohol content of a solution containing amyloid-β changes the solution’s polarity which in turns causes a structural transformation in the strand-like peptides. This transformation is characterized by coils forming between the peptides, creating a single helix structure. Amyloid-β in this structure does not dissolve well in water due to the coils and so aggregates as amyloid fibrils much more easily than amyloid-β in its normal state. However, in many cases these coils do dissolve and do not lead to any further aggregation. By the same token, a decrease in the fat or alcohol content of the solution results in less coil formation and higher rates of formation of oligomer and protofibril, two other types of protein aggregate structures. Depending on changes in solution pH and ionic strength, these structures can transform again into amyloid fibrils.

 Although there have been many studies about amyloid-β peptides forming amyloid fibrils or oligomers, this study is the first to identify aggregate formation pathways at the molecular level. Recently, there have been several studies about the development of new medications for preventing dementia by blocking amyloid plaque production, but none have been successful. The lack of molecular research similar to that conducted in this study is a contributing factor to this lack of progress.

 To examine amyloid fibril formation at the molecular level, the research team integrated methods from biophysics, cellular biology, and animal studies in their research methods. The team developed an ultrasound technology that accelerated intermediary processes in the formation of amyloid fibrils from amyloid-β peptides to examine aggregate formation within a short period of time.

 The KAIST team conducted toxicity testing and aggregate analysis and the Korea Brain Research Institute (“KBRI”) conducted mouse testing and analysis. The ROK team (KAIST, Sookmyung Women’s University, Konkuk University, KBRI) collectively collaborated with the USA team (University of Michigan) on studying molecular dynamics and conducting nuclear magnetic resonance analysis. The Japan team (Osaka University, Tohoku University) conducted oligomer detection and analysis. KBSI was in charge of overall biophysics testing and analysis which was conducted using high field nuclear magnetic resonance equipment, ultra-high voltage electron microscopes for studying living organisms, and an aberration-corrected ultra-high resolution transmission electron microscope. The use of such technology during analysis played an important role in confirming whether and what kind of aggregates had formed.

 The results of this study were published in the online version of the international academic journal ACS Nano: Diverse Structural Conversion and Aggregation Pathways of Alzheimer’s Amyloid-β (1-40) (First author: Lin Yuxi; Professor: Lee Young-ho) on July 16, 2019.

 Dr. Lee Young Ho of KBSI stated that the successful identification of the mechanisms, structures, and varying types of aggregate formation in proteins will play an important role in the development of innovative medications for treating dementia, Parkinson’s disease, Type II diabetes, Lou Gehrig’s disease, cataracts, prion diseases, and other diseases that are caused by the formation of amyloid fibrils. He added that, in the near future, these results will play a leading role in studies for understanding the fundamental concepts of, analyzing, and developing treatments for important diseases characteristic of an aging society.

 

 Source : The Korea Basic Science Institute(KBSI)'s official website