In the brains of people with Alzheimer’s disease, amyloid-β (Aβ) peptides assemble into fibrils, which in turn tangle together to form amyloid plaques. In a new study, chemists designed macromolecules that redirect Aβ’s aggregation from microscale fibrils to nearly spherical nanostructures (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja501102f). The findings could help illuminate how amyloid fibrils grow, as well as suggest new therapeutic strategies for the disease, the researchers say.
Amyloid fibril growth has two stages: a slow nucleation phase characterized by weak interactions between Aβ monomers, and an elongation phase in which the amyloid chain grows rapidly. Jeffrey S. Moore and his colleagues at the University of Illinois, Urbana-Champaign reasoned that by interfering with the nucleation phase, they could perhaps disrupt amyloid assembly. So they synthesized inhibitor molecules that contained multiple copies of an Aβ-binding peptide attached to a linear copolymer backbone. The peptide they used binds to a specific region of Aβ that interacts with other Aβ monomers.
The team found that when a polymer-peptide conjugate containing 21 copies of the Aβ-binding peptide was added to an equal amount of Aβ peptide, the conjugate completely suppressed fibril formation. But, at an equivalent concentration, the binding peptide alone did not affect how Aβ assembled. The researchers found that in the presence of the polymer-peptide conjugate, Aβ formed nearly spherical structures about 30 nm in diameter, which surprised the chemists.
“We were trying to inhibit fibrillar growth,” says Moore. “The reproducible appearance of nanostructures of discrete size and shape was completely unexpected.” The researchers are currently investigating the composition of these nanostructures. Understanding the structures and how they form may suggest new ways to prevent or disrupt amyloid aggregation, Moore says.