The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide

Jitka Petrlova, T. Kalai, Izumi Maezawa, Robin Altman, Ghimire Harishchandra, Hyun Seok Hong, Daniel A. Bricarello, Atul N. Parikh, Gary A. Lorigan, Lee Way Jin, K. Hideg, John C. Voss

Research output: Contribution to journalArticle

12 Citations (Scopus)

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. Methodology/Principal Findings: 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 posses both antioxidant properties and the ability to disrupt AβO species.

Original languageEnglish
Article numbere35443
JournalPLoS One
Volume7
Issue number4
DOIs
Publication statusPublished - Apr 30 2012

Fingerprint

Oligomers
Aptitude
Toxicity
peptides
toxicity
Peptides
amyloid
Alzheimer disease
Fluorenes
Alzheimer Disease
electron paramagnetic resonance spectroscopy
Spin Labels
Amyloid Precursor Protein Secretases
Cytoprotection
Electron Spin Resonance Spectroscopy
etiology
Pathologic Processes
mechanism of action
pathogenesis
Amyloid

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Petrlova, J., Kalai, T., Maezawa, I., Altman, R., Harishchandra, G., Hong, H. S., ... Voss, J. C. (2012). The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide. PLoS One, 7(4), [e35443]. https://doi.org/10.1371/journal.pone.0035443

The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide. / Petrlova, Jitka; Kalai, T.; Maezawa, Izumi; Altman, Robin; Harishchandra, Ghimire; Hong, Hyun Seok; Bricarello, Daniel A.; Parikh, Atul N.; Lorigan, Gary A.; Jin, Lee Way; Hideg, K.; Voss, John C.

In: PLoS One, Vol. 7, No. 4, e35443, 30.04.2012.

Research output: Contribution to journalArticle

Petrlova, J, Kalai, T, Maezawa, I, Altman, R, Harishchandra, G, Hong, HS, Bricarello, DA, Parikh, AN, Lorigan, GA, Jin, LW, Hideg, K & Voss, JC 2012, 'The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide', PLoS One, vol. 7, no. 4, e35443. https://doi.org/10.1371/journal.pone.0035443
Petrlova, Jitka ; Kalai, T. ; Maezawa, Izumi ; Altman, Robin ; Harishchandra, Ghimire ; Hong, Hyun Seok ; Bricarello, Daniel A. ; Parikh, Atul N. ; Lorigan, Gary A. ; Jin, Lee Way ; Hideg, K. ; Voss, John C. / The influence of spin-labeled fluorene compounds on the assembly and toxicity of the aβ peptide. In: PLoS One. 2012 ; Vol. 7, No. 4.
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