Proc. Natl Acad. Sci. USA 110, 2798–2803 (2013)

Credit: © 2013 NATIONAL ACADEMY OF SCIENCES

In the initial steps of amyloid fibril formation, proteins or peptides self-associate to form small oligomers. The addition of more polypeptide species leads to larger aggregates, termed proto-fibrils, and eventually mature amyloid fibrils. Gathering detailed information on the structure and growth of the intermediate structures could help develop methods to interrupt or reverse the fibrillization process, which could lead to new treatments for a variety of amyloid-related diseases.

Human islet amyloid polypeptide (hIAPP) is found in amyloid deposits in patients with type 2 diabetes. To find out more about what occurs during fibrillization of hIAPP, a team led by Mingdong Dong at Aarhus University, Denmark, investigated the aggregation of a decapeptide (hIAPP20-29). This oligopeptide is thought to be the region of the protein that initiates fibril formation of hIAPP. Dong and co-workers used a combination of atomic force microscopy and microsecond force microscopy to follow the formation and changes in morphology of the peptide nanostructures throughout the aggregation process — from small strands through to helical fibrils. They also measured the rate at which structures thickened, which is a key property for growth and maturation of fibrillar structures.

Initially the decapeptide self-assembled to form thin strands during the so-called lag phase. As aggregation progressed into the elongation phase, the thin ribbons became wider. After a couple of hours, some of the ribbons began to twist and continued to gradually thicken. Multi-strand mature helical fibrils were then formed from the twisted ribbons; however, instead of forming helical fibrils, some of the flat ribbons thickened further and formed large flat ribbons. These larger flat ribbons are still present at the end of the fibrillization process, which proves that the ribbon structures and helical fibrils can co-exist in solution and that not all proto-fibrils transform into mature amyloid fibrils in the case of the hIAPP decapeptide. Dong and co-workers suggest that the thickening of ribbons makes them energetically stable, which enables them to co-exist with the helical fibrils.