Nano-scale properties of the amyloid life-cycle

Speaker:          Wei-Feng Xue
Department:   School of Biosciences, University of Kent
Subject:          Nano-scale properties of the amyloid life-cycle
Location:        TU Delft
Date:              12-05-2016

Author: Carolien Bastiaanssen

Amyloids are protein aggregates that often form a fibrillar structure with a width of ~10 nm. They come in a variety sizes, ranging from ~10 nm to several μm in length. Xue refers to this length scale as the mesoscopic scale. Some amyloids have a functional role, but they are the subject of many studies because they are involved in multiple diseases such as Alzheimer’s disease, Parkinson’s disease and type II diabetes mellitus. Some amyloids are transmissible, in this case they are called prions. Examples of diseases where prions are involved are Creutzfeldt-Jakob disease and scrapie. Nowadays there is no sharp boundary anymore between amyloids and prions due to the realization that many amyloids that were thought not to be transmissible now appear to be transmissible. One of the questions that Xue wants to answer is what makes an amyloid transmissible.

Fibrils of different lengths. (Top: EM images, bottom: AFM images)
                            Fibrils of different lengths. (Top: EM images, bottom: AFM images) [1]

Before being able to answer this question, Xue needs to understand how amyloids assemble. This is a slow and complex process, which is often compared with a life cycle. When monomers are put into solution it takes quite some time before they nucleate. This waiting time is called the lag phase. Next an exponential growth phase follows, until a plateau is reached. The long lag time causes diseases such as Alzheimer’s disease to primarily affect the elderly. However, in case of prion diseases the long lag time is skipped because of the transmission of preformed polymers. After polymers have formed, they can fragment and new polymers can grow from these fragments. This process is called seeding. Many question remain, regarding the life cycle of amyloids. It is for example still unclear how monomers form seeds and what the exact molecular structure is of these seeds.

In order to gain more knowledge about amyloids, Xue studies their mechanical properties. He uses atomic force microscopy (AFM) to characterize the size distribution, persistence length and force resistance of amyloids. AFM has the advantage that it allows the study of individual amyloid particles in great detail. Because they analyze many samples, Xue and his team developed a tool (trace-y) to automatically trace amyloid fibrils.

One of the experiments Xue and his team performed, involved measuring the length of amyloids and then studying their interaction with membranes. They found that long fibrils are less harmful for cells than short fibrils. They measured a cell viability of 82% for long fibrils and 36% for short fibrils. The reason why shorter fibrils have a higher cytotoxicity than longer fibrils is still a matter of debate. Research suggests that the ends of the fibrils interact with the membrane and cause damage, in this case a more fragmented amyloid would indeed be more lethal to cells than one large amyloid. Therefore, Xue would not pursue a treatment of e.g. Alzheimer’s disease which is aimed at dissolving prions. He would opt for stabilizing the prions that are there already or in case you can start treatment early, prevent amyloids from forming at all.

The crucial part of the amyloid life cycle is the fragmentation process. Therefore it is of large interest to Xue. Many aspects of this process still require research to elucidate the underlying mechanisms. It is for example unknown what triggers fibrils to break and how stable different amyloids are. Xue and his team for example study the stability of fibrils towards breakage using AFM and they check whether the obtained data fit with the theoretical model they developed.

All together, it was a very interesting talk by Xue. Although I did not have any prior knowledge on amyloids, everything was clear to me. Xue was very enthusiastic and I could sense the passion he has for his work. It was nice to see that in this research physics and biology come together and this a good example of a field of research in which a Nanobiologist could be of good use.

1. W. F. Xue et al., Fibril fragmentation enhances amyloid cytotoxicity. J. Biol. Chem. 284, 34272-34282 (2009).

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