03.07.18 15:07

Alzheimer’s research: Article in Chemical Science

Toxic protein clumps can prevent their own disassembly

By: Editor / Arne Claussen

Many neurodegenerative conditions, including Alzheimer’s disease, are triggered by the clumping of certain protein molecules.

Together with colleagues in the USA, researchers at Heinrich Heine University Düsseldorf (HHU) and Jülich Research Centre have now discovered that the small and particularly toxic aggregates known as oligomers protect themselves against their own disassembly and can thus remain toxic for longer. Their results have now been published in the “Chemical Science” journal.

Oligomers (left) actively prevent their disassembly into fibrils (threads in the right-hand picture). (Illustration: Wolfgang Hoyer / HHU)

Oligomers are aggregates made up of a small number of protein molecules. In the case of Alzheimer's disease, for example, this is the protein amyloid beta (Aβ). Apart from oligomers, larger structures can also develop out of these proteins, i.e. fibrils and ultimately plaques, which form from fibrils. All these substances are toxic to nerve cells. It is already known that the oligomers are the most dangerous, since even in very small quantities they damage or even kill off nerve cells.

Together with colleagues from the University of South Florida, the researchers in Düsseldorf and Jülich led by Dr. Wolfgang Hoyer of HHU's Institute of Physical Biology examined how oligomers develop and how they are disassembled over the course of time to form fibrils. It emerged that oligomers and fibrils form independently of each other and both compete for the same supply of amyloid beta building blocks. Although the oligomers are indeed more short-lived than the fibrils and disintegrate after a certain time into their individual components, the researchers found out that they actively disrupt fibril formation and are thus able to protect themselves from disassembly.

"Our results explain why the severity of Alzheimer's disease depends only minimally on the number of plaques. There is a far greater correlation between the clinical symptoms and the number of oligomers," says Dr. Hoyer, expounding the far-reaching consequences of the study. This would mean that the oligomers are also a prime target when developing drugs to treat Alzheimer's disease.


Original article

Filip Hasecke, Tatiana Miti, Carlos Perez, Jeremy Barton, Daniel Schölzel, Lothar Gremer, Clara S. R. Grüning, Garrett Matthews, Georg Meisl, Tuomas P. J. Knowles, Dieter Willbold, Philipp Neudecker, Henrike Heise, Ghanim Ullah, Wolfgang Hoyer and Martin Muschol, Origin of metastable oligomers and their effects on amyloid fibril self-assembly, Chemical Science, 13.06.2018

 

DOI: 10.1039/c8sc01479e

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