- Speaker: Wei-Feng Xue
- Department: School of Biosciences, University of Kent
- Subject: Nano-scaled properties of the amyloid life-cycle
- Location: TU Delft
- Date: 12-05-2016
- Author: Katja Slangewal
It is well known that viruses and bacteria can cause diseases. However, they are not the only disease causing agents. Type II diabetes, Alzheimer, Parkinson and Mad-cow disease are for instance associated with amyloids and prions. Amyloids and prions are aggregates of proteins and/or peptides. Prions are usually seen as the transmissible variant of amyloids. However, Xue showed that the border between them gets more blurry over time.
Amyloids and prions both form fibrils with a diameter of approximately 10nm and a length between several nanometers and hundreds of micrometers. Later it will be shown that the length has a large influence on the biological activity. Since amyloids are shown to have an influence at several diseases, it is important to learn more about these bio-structures. Xue and his team want to find the growth rate, deposition and cytotoxicity of amyloids. He also wants to know more about the propagation and transmission of prions.
Figure 1: Amyloids have a large size range. A) shows the oligomers before polymerization. B) shows short fibrils. C) shows long fibrils. 
The first thing Xue showed was the rate of assembly of amyloids. This appeared to be very slow and complex. The polymerization of amyloids has a very high energy barrier. This is somehow good news for elderly people who are being infected with an amyloid causing Alzheimer. The time it takes for the amyloids to form enough fibrils to be harmful is probably longer than the time the elderly people still have left. However, this is only true when the fibrils have to form from scratch. When you are infected with preformed fibrils, the long lag phase is skipped and the amyloids can grow faster. This is called seeding.
Although amyloids are not considered to be alive, they have something like a life cycle. They can form de novo by nucleation. After growing, they can fragmentation can occur. The smaller polymers can grow again until a next fragmentation. It appears that fragmentation accelerates the growth of amyloids. Two samples were tested, one with large amyloids and one with small amyloids. It appeared that the small amyloids grow quicker than the larger ones. Also, the small ones appeared to be more harmful to membranes. This was shown by measuring the membrane disruption for both samples (figure 1). Next, the amyloids were added to tumor cells. The viability of the tumor cells was measured. For the large amyloids the viability was 82% and for the small amyloids it was 36%. Finally, the stability was measured by applying a mechanical force to the amyloids. The results show that the longer fibrils fragmentize easier and shorter fibrils are more stable.
Figure 2: Left) shows liposomes and short fibrils. The arrowheads show disrupted liposomes. Right) shows liposomes and long fibrils. Almost no disruption of liposomes was observed. 
Summarizing the results, Xue proposed a model which shows the ‘life’ of an amyloid. First the amyloid grows for a long time, than it fragmentizes before it reaches a steady state. The growth and fragmentizing phase take around 109 seconds, which equals approximately 30 years. The experiments showed that the amyloids are most dangerous when they are short.
The last experiment Xue described was about the transmissibility of prions. He used synthetic prions that were not capable of causing harm and introduced them to yeast. These prions had never seen yeast before, but they were able to induce a certain phenotype when infecting them. This phenotype showed the transmissibility. It appeared that the smallest fibrils had the highest transmissibility.
So amyloids and prions can cause severe diseases. This means it is necessary to study their properties. The biological activity of the amyloids is dependent on the length of the fibrils. It was shown that the smaller the fibrils the more harm they can induce. Also, the transmissibility of prions increases when the length decreases. More research has to be done in order to find a way to prevent amyloid/prion based diseases.
Wei-Feng Xue gave a nice talk. He was very enthusiastic about his work and he was smiling during the entire talk. This made his talk very lively. He clearly stated the importance of his work and the explanation of the results was also very good. Every graph was discussed properly. He didn’t go to deep into the methods he used. This made it easier for me to understand everything he was saying. I think this talk was the first talk in which I didn’t feel like missing a large part of the background information. I liked the talk, but I don’t think I want to do research to amyloids or prions myself. I like living and more complex cells better than these fibrils.
: A. Relini, N. Marano, A. Gliozzi (2014) Misfolding of amyloidogenic proteins and their interactions with membranes. Biomolecules. 4(1): 20-55
: L. Milanesi et al. (2012) Direct three-dimensional visualization of membrane disruption by amyloid fibrils. PNAS. 109(50): 20455-20460