Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure

Alzheimer's disease is characterized by the presence of extracellular plagues comprised of amyloid beta (AS) peptides. Soluble oligomers of the AS peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Single particle analyses of A beta oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of A beta) prevent and disrupt oligomeric assemblies of AS in solution. Furthermore, the circular dichroism (CD) spectrum of untreated A beta shows a continuous, progressive change over a 24-hour period, while the spectrum of AS treated with SLF remains relatively constant following initial incubation. These findings suggest the conformation of AS within the oligomer provides a complementary determinant of A beta toxicity in addition to oligomer growth and size. Although SLF does not produce a dominant state of secondary structure in yap, it does induce a net reduction in beta secondary content compared to untreated samples of All The FCS results, combined with electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibit the growth of A beta oligomers and disrupt existing oligomers, while retaining AS as a population of smaller, yet largely disordered oligomers. (C) 2015 Elsevier B.V. All rights reserved.