Physicists from the University of Luxembourg together with scientists from Australia, China and Switzerland have recently studied amyloid diseases such as Alzheimer’s or Parkinson’s by using a particle accelerator. The results have been published in the Biophysical Journal in April 2020.
Huge international effort to find treatments…
Failed or nearly-useless cures for amyloid diseases such as Alzheimer’s or Parkinson’s have been a common output of the huge international effort to treat this family of tragic and expensive conditions. The US government will spend more than 2 billion dollars on amyloid disease research in 2020 (Source: Sciencemag), while even tiny Luxembourg expects to spend at least 2-3 million euro to support a centre of excellence in Parkinson’s disease (Source: FNR). This large and steady flow of investment has generated hundreds of candidate medicines, nearly all of which were rejected after proving to be ineffective. Significant success against light-chain amyloidosis has come from targeting the raw material before it can form amyloid (Source: PNAS) however this strategy is unlikely to work in all cases.
…but not really effective until now
“One reason that many candidate therapies failed was that they targeted mature amyloid fibrils, the sticky aggregates formed in the brains of affected patients, which are large enough to be observed with a normal microscope. These aggregates are an obvious candidate for therapy, such as using antibodies to direct the immune system to destroy them, however this approach has failed too often, and it now seems that smaller and more dynamic objects are to blame for most or all of the damage caused by amyloid aggregation,” explains Josh Berryman, researcher within the Department of Physics and Materials Science at the University of Luxembourg.
Studying small objects with particle accelerator
“The amyloid aggregates causing the most damage to cells are so small, only a few atoms thick, that they can’t easily be seen with a normal microscope,” continues Dr Berryman. Scientists from the University of Luxembourg, La Trobe University (Australia), Shanghai University (China) and ETH Zurich (Switzerland) have collaborated to instead use a particle accelerator (the Australian Synchrotron) to investigate these tiny and short-lived objects using high-energy radiation to map out their structures.
The surprise after processing the synchrotron data and relating it to computer simulations, is that the small aggregates are completely different to the much bigger final products: while in mature amyloid neighbouring molecular chains typically point in the same direction (they are parallel), in the first small aggregates to be formed the chains point in opposite directions (they are antiparallel), giving a completely different recognition for antibodies.
“It still isn’t clear how antiparallel aggregates are replaced by parallel, or if one is really more toxic that the other, or how many real diseases will reproduce the behaviour seen in a test-tube: but with new candidate drug targets the worldwide machine of research and development has the pathways that it needs to keep moving on,” says Dr Berryman with enthusiasm.
Article: “Amyloid Evolution: Antiparallel replaced by Parallel”, Biophysical Journal, April 2020