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

摘要

Alzheimer’s disease is characterized by the presence of extracellular plaques comprised of amyloid betaud(Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunctionudassociated with Alzheimer's disease. Single particle analyses of Aβ oligomers in solution by fluorescenceudcorrelation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenesud(SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomericudassemblies of Aβ in solution. Furthermore, the circular dichroism (CD) spectrum of untreated Aβ showsuda continuous, progressive change over a 24-hour period, while the spectrum of Aβ treated with SLFudremains relatively constant following initial incubation. These findings suggest the conformation of Aβudwithin the oligomer provides a complementary determinant of Aβ toxicity in addition to oligomer growthudand size. Although SLF does not produce a dominant state of secondary structure in Aβ, it does induce audnet reduction in beta secondary content compared to untreated samples of Aβ. The FCS results, combinedudwith electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibitudthe growth of Aβ oligomers and disrupt existing oligomers, while retaining Aβ as a population of smaller,udyet largely disordered oligomers.