The Role of α-sheet in Amyloid Oligomer Aggregation and Toxicity

A major barrier to developing effective treatments and diagnostics for amyloid diseases is the inability of traditional protein structure characterization methods to elucidate the structure of the toxic oligomers that form during amyloidogenesis. Some years ago, our lab "discovered" a novel protein secondary structure in molecular dynamics simulations of multiple unrelated amyloid proteins, which we call alpha-sheet. We hypothesize that alpha-sheet plays an important role in amyloid aggregation and oligomer toxicity. De novo monomeric alpha-sheet peptides designed to be complementary to the structure observed in simulations inhibit amyloid aggregation and toxicity and specifically bind to the toxic oligomeric species in a variety of unrelated mammalian and bacterial amyloid systems associated with a range of diseases. Furthermore, spectroscopic analysis of alpha-sheet structure, including nuclear magnetic resonance (NMR dagger), circular dichroism (CD), and Fourier-transform infrared spectroscopy (FTIR), correspond well to values predicted for alpha-sheet. These alpha-sheet designs are now being tested for their ability to detect and neutralize toxic oligomers in animals and in patient samples, demonstrating the potential of this nonstandard secondary structure as a target for therapeutic and diagnostic agents for amyloid diseases.