Amyloid-beta (A-beta) aggregates are tangles of proteins most notably associated with neurodegenerative diseases such as Alzheimer’s. Despite its constant stint in the limelight, however, researchers have been unable to get a good understanding of how A-beta comes together and breaks apart.
“The way A-beta behaves in a variety of environments, including the human brain, is elusive,” said Brian Sun, an electrical systems and engineering alumnus of Washington University in St. Louis who is now an MD/PhD student at the School of Medicine.
“There’s an understanding of growth and decay that isn’t fully fleshed out,” he added.
That’s going to change, thanks to research recently published by Sun with colleagues in Matthew Lew’s lab in the Preston M. Green Department of Electrical & Systems Engineering at WashU’s McKelvey School of Engineering.
In first-of-its-kind work, Sun and colleagues were able to measure amyloid fibril beta-sheet assemblies, the underlying girders of the protein conglomeration, while they were changing. Previous high-resolution microscopy studies have only gotten static shots.
“We wanted to look specifically at dynamics of the underlying structure of A-beta that could be responsible for the changes we’re seeing, not just changes in the overall shape,” said Sun, the paper’s first author.
Lew used Lego bricks in an analogy, noting that current imaging technology shows you the full Lego building but not a look at how individual bricks are organized.
“The individual proteins are always changing in response to their environment,” said Lew, an associate professor. “It is like having certain Lego bricks causing other bricks to change their shape. The changing architecture of the proteins and the assembled aggregates together leads to the complexity of neurodegenerative disease.”
The Lew lab has developed a new type of imaging tech that allows researchers to see the orientation and other minute details in nanostructures of biological systems that were previously invisible. Their technique — single-molecule orientation–localization microscopy (SMOLM) — uses flashes of light from chemical probes to visualize the sheets of peptides underlying Aβ42, one kind of A-beta peptide.
Using SMOLM lets them look at individual orientation of the underlying beta-sheets to see the relationship between their organization and how that relates to the amyloid protein’s overall structure.