A team of scientists, based at Swiss Federal Institute of Technology Lausanne (EPFL) with collaborators at Ulm University in Germany, University of Modena and Reggio Emilia in Italy, and MIT, have developed custom nanoparticles for high-resolution detection of amyloid fibrils, those associated with Alzheimer’s and Parkinon’s. The newly developed technology enables researchers to investigate the specific fibril architectures in deceased patients who had amyloid-based diseases, allowing rapid high-resolution imaging of fibrils.
Many diseases, including Alzheimers, Parkinson’s, and others, are associated with amyloid fibril formation. These diseases manifest themselves similar to how prions behave, where one misfolded protein can encourage other proteins to misfold as well, creating large plaques of protein aggregates in the brain. Surprisingly, these protein plaques can form various different structures (helical, straight, ribbon, etc), and scientists do not understand why. Current technologies for imaging amyloid fibrils require large quantities of protein, or have low signal to noise ratios, making data interpretation difficult. To address these challenges, this team of scientists developed nanoparticles to bind the surface of amyloid fibrils and thus improve contrast when imaged using cryo-electron microscopy.
The team tested various binding molecules on the surface of the nanoparticles. They found that zwitterionic molecules, those that have both positive and negative charges on the surface, did not interact with the amyloid fibrils, and positively charged ligands had nonspecific binding, leading to aggregate formation. The team also discovered that negatively charged molecules, called MUS, attached to amyloid fibrils, and incorporated hydrophobic ligand, called OT, to improve contact with the fibrils. In this way, the team identified MUS: OT A as the appropriate surface molecule to help bind gold nanoparticles to the amyloid fibrils.
This finding can help scientists better understand the biochemical
underpinnings of amyloid fibril formation and may serve as a valuable
diagnostic tool in the future.