A change in the shape of a protein, rather than its size, is the driving force in small protein aggregates morphing into the insoluble structures present in the brains of Alzheimer’s patients — a process known as nucleation, according to a study.
Because the aggregates, known as amyloid-beta oligomers, are increasingly seen as enemies of Alzheimer’s disease mechanisms, insights into the processes governing amyloid-structure conversion may offer new possibilities for preventing the disease.
The study, “Kinetics of spontaneous filament nucleation via oligomers: Insights from theory and simulation,” was a collaboration between scientists at University College London and the University of Cambridge in the U.K, and Harvard University. The work was published in the Journal of Chemical Physics.
Nucleation is widespread in nature. An example is collecting enough water vapor molecules to form a cloud or ice crystal.
Nucleation is also present in the body, where protein filaments, or sheets, play many important roles. When the process occurs in the wrong place, however, it can cause disease, such as Alzheimer’s.
“Perhaps an intuitive example of nucleation would be the way in which a quiet dinner party suddenly transforms into a dancing one; such a transition usually requires several people to start dancing at once, acting as a ‘nucleus’ around which the dancing party assembles,” Anđela Šarić, lead co-author at University College London and the University of Cambridge, said in a press release.
“As commonly observed, if this group of dancers is too small, it tends to be ignored; however, above a certain size, this dancing nucleus attracts more and more people, eventually dominating the room,” added Thomas Michaels, the other lead author.
The smallest number of dancing people, or amyloid oligomers, needed to start the transformation is referred to as the “critical nucleus.”
Using advanced computer simulations, the research team showed that when individual proteins, known as monomers, assemble into oligomers, they need to change their three-dimensional shape before the larger protein aggregate can start building.
Earlier research had suggested that it was the size of the oligomers that was critical for triggering the formation of insoluble fibrils.
“Understanding which microscopic-level steps are determining for the formation of protein fibrils can provide invaluable information for designing rational therapies aimed at suppressing pathogenic oligomer generation,” Šarić said.