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Title: 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 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. The FCS results, combined with electron paramagnetic resonance spectroscopy and circular dichroism spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers while retaining Aβ in a largely disordered state. Furthermore, while the ability of SLF to block Aβ toxicity correlates with a reduction in oligomer size, our results suggest the conformation of Aβ within the oligomer determines the toxicity of the species. Attenuation of Aβ toxicity, which has been associated primarily with the soluble oligomeric form, can be achieved through redistribution of the peptides into smaller oligomers and arrest of the fractional increase in beta secondary structure.
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [4] ;  [4] ;  [3] ;  [1] ;  [1]
  1. Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Science Directorate
  3. Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine
  4. Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry
Publication Date:
OSTI Identifier:
Report Number(s):
Journal ID: ISSN 1570-9639
DOE Contract Number:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochimica et Biophysica Acta. Proteins and Proteomics; Journal Volume: 1854; Journal Issue: 12
Research Org:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org:
Country of Publication:
United States