title: Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure.
abstract: Alzheimer's disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Single particle analyses of Aβ 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 Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. Furthermore, the circular dichroism (CD) spectrum of untreated Aβ shows a continuous, progressive change over a 24-hour period, while the spectrum of Aβ treated with SLF remains relatively constant following initial incubation. These findings suggest the conformation of Aβ within the oligomer provides a complementary determinant of Aβ toxicity in addition to oligomer growth and size. Although SLF does not produce a dominant state of secondary structure in Aβ, it does induce a net reduction in beta secondary content compared to untreated samples of Aβ. The FCS results, combined with electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers, while retaining Aβ as a population of smaller, yet largely disordered oligomers.
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis CA 95616, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Altman
authors.affiliation: Physical and Life Science Directorate, Lawrence Livermore National Laboratory, Livermore CA 94550, USA.
authors.forename: Sonny
authors.initials: S
authors.lastname: Ly
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis CA 95616, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hilt
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis CA 95616, USA.
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento CA 95817, USA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, H-7624 Pécs, Szigeti st. 12. Pécs, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.affiliation: Institute of Organic and Medicinal Chemistry, University of Pécs, H-7624 Pécs, Szigeti st. 12. Pécs, Hungary.
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.affiliation: M.I.N.D. Institute and Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento CA 95817, USA.
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.affiliation: Physical and Life Science Directorate, Lawrence Livermore National Laboratory, Livermore CA 94550, USA.
authors.forename: Ted A
authors.initials: TA
authors.lastname: Laurence
authors.affiliation: Department of Biochemistry & Molecular Medicine, University of California Davis, Davis CA 95616, USA. Electronic address: jcvoss@ucdavis.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002460:Cell Line; D002942:Circular Dichroism; D005449:Fluorenes / Q000737:chemistry*; D006801:Humans; D017433:Protein Structure, Secondary; D013113:Spin Labels
chemical_list: D016229:Amyloid beta-Peptides; D005449:Fluorenes; D013113:Spin Labels
keywords: Amyloid beta; Circular dichroism spectroscopy; Fluorescence correlation spectroscopy; Oligomer; Secondary structure; Spin-labeled fluorene