The clumping of beta-amyloid protein into plaques that clog up the brain is a key hallmark of Alzheimer’s disease. Much research into the causes and treatment of the disease relies on techniques that characterize this process. Now, a new study challenges a commonly held view about the shape and composition of the initial structures that form when the beta-amyloid molecules come together.
The study, led by the Institute for Research in Biomedicine, Barcelona (IRB Barcelona) in Spain, is published in the journal Scientific Reports.
It finds that a technique used by Alzheimer’s disease researchers to analyze the beta-amyloid clumps as they initially come together is flawed because of conclusions it draws about the shapes of the aggregated proteins and the number of molecules they contain. The technique is called SDS-PAGE.
For their study, the team focused on “Abeta fibrils” – the initial structures that form in the brain when the beta-amyloid proteins begin to clump together. Lead investigator Dr. Natàlia Carulla, a specialist in biomedical chemistry at IRB Barcelona, explains why this work is important:
“Comprehensive knowledge of the number of units and conformation of Abeta at the initial stages of aggregation is crucial for the design of drugs capable of breaking them up or preventing their formation.”
The team chose to study two of the most common forms of Abeta – Abeta 40 and Abeta 42 – comprising 40 and 42 amino acids, respectively, with Abeta 42 as the variant most commonly found in Alzheimer’s disease.
The researchers note that when SDS-PAGE is used to analyze the structures of Abeta 40 and Abeta 42, it shows that Abeta 40 self-aggregates to sequentially form dimers (two units), trimers (three units) and tetramers (four units), while Abeta 42 forms mainly through pentamers (five units) and hexamers (six units).
This means that, since Abeta 42 is thought to have a more prominent role in Alzheimer’s disease, many studies have concluded that pentamers and hexamers are the basic building blocks of beta-amyloid fibrils in Alzheimer’s.
These assumptions are widespread in Alzheimer’s research because of the popularity of SDS-PAGE (it only needs a small amount of sample) and the fact the model forms a key element in a small set of studies that have been cited over 1,000 times, note the researchers.
Because of the assumption that Abeta 42 formed mainly pentamers and hexamers, it was thought that these formed defined structures called “beta-sheets,” so drug-developers have been working on the assumption that the agents have to tackle the beta-sheet structure.
However, Dr. Carulla and colleagues say there is a flaw in SDS-PAGE that causes it to show Abeta 42 forms mainly through pentamers and hexamers.
Using a new technique based on mass spectrometry, they observed that both Abeta 40 and Abeta 42 form dimers, trimers and tetramers and that in these initial stages these aggregates are spherical and lack a defined structure.
The researchers suggest the assumption that drugs have to interfere with the beta-sheet structure in order to target the clumping process of beta-amyloid in Alzheimer’s disease should be reconsidered – and they recommend caution when using SDS-PAGE to study Abeta aggregates.
Dr. Carulla comments on the reaction their findings may trigger:
“This study will lead to reservations on the part of the scientific community and that is why we have been thorough and present methodologically robust data.”
She and her colleagues are now looking for molecules that might prevent the formation of the initial Abeta structures.
Another promising area of research in Alzheimer’s disease has been spurred by the discovery that the brain has “small heat shock proteins” that prevent uncontrolled protein clumping. Medical News Today recently learned of a study that reveals two ways in which small heat shock proteins interact with beta-amyloid to prevent clumping.