title: The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide.
abstract: BACKGROUND
  The deposition and oligomerization of amyloid β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD). Aβ peptide arises from cleavage of the membrane-associated domain of the amyloid precursor protein (APP) by β and γ secretases. Several lines of evidence point to the soluble Aβ oligomer (AβO) as the primary neurotoxic species in the etiology of AD. Recently, we have demonstrated that a class of fluorene molecules specifically disrupts the AβO species.
  
  
  RESULTS
  To achieve a better understanding of the mechanism of action of this disruptive ability, we extend the application of electron paramagnetic resonance (EPR) spectroscopy of site-directed spin labels in the Aβ peptide to investigate the binding and influence of fluorene compounds on AβO structure and dynamics. In addition, we have synthesized a spin-labeled fluorene (SLF) containing a pyrroline nitroxide group that provides both increased cell protection against AβO toxicity and a route to directly observe the binding of the fluorene to the AβO assembly. We also evaluate the ability of fluorenes to target multiple pathological processes involved in the neurodegenerative cascade, such as their ability to block AβO toxicity, scavenge free radicals and diminish the formation of intracellular AβO species.
  
  
  CONCLUSIONS
  Fluorene modified with pyrroline nitroxide may be especially useful in counteracting Aβ peptide toxicity, because they possess both antioxidant properties and the ability to disrupt AβO species.
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Jitka
authors.initials: J
authors.lastname: Petrlova
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Izumi
authors.initials: I
authors.lastname: Maezawa
authors.forename: Robin
authors.initials: R
authors.lastname: Altman
authors.forename: Ghimire
authors.initials: G
authors.lastname: Harishchandra
authors.forename: Hyun-Seok
authors.initials: HS
authors.lastname: Hong
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bricarello
authors.forename: Atul N
authors.initials: AN
authors.lastname: Parikh
authors.forename: Gary A
authors.initials: GA
authors.lastname: Lorigan
authors.forename: Lee-Way
authors.initials: LW
authors.lastname: Jin
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: John C
authors.initials: JC
authors.lastname: Voss
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D005449:Fluorenes / Q000737:chemistry / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000378:metabolism*; D006801:Humans; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000378:metabolism; D013113:Spin Labels; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D005449:Fluorenes; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; D013113:Spin Labels; D013778:Tetrazolium Salts; D013844:Thiazoles; C041509:fluorene; C022616:thiazolyl blue