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

Robin Altman, Sonny Ly, Silvia Hilt, Jitka Petrlova, Izumi Maezawa, Tamás Kálai, Kálmán Hideg, Lee-Way Jin, Ted A. Laurence, John C Voss

Research output: Contribution to journalArticle

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1860-1870
Number of pages11
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1854
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • Amyloid beta
  • Circular dichroism spectroscopy
  • Fluorescence correlation spectroscopy
  • Oligomer
  • Secondary structure
  • Spin-labeled fluorene

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Analytical Chemistry
  • Molecular Biology

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