Temporal relations among amyloid β-peptide-induced free-radical oxidative stress, neuronal toxicity, and neuronal defensive responses

Servet M. Yatin, Marina Aksenova, Michael Aksenov, William R. Markesbery, Timothy Aulick, D. Allan Butterfield

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65 Scopus citations


Amyloid β-peptide (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is hypothesized to be a key factor in the neurodegeneration seen in AD. Recently it has been shown that the neurotoxicity of Aβ occurs in conjunction with free-radical oxidative stress associated with the peptide. In the present study, we investigated the temporal relations among the formation of Aβ-associated free radicals, the oxidative damage to, and the activation of antioxidant defense mechanisms in rat embryonic hippocampal neuronal culture subjected to toxic Aβ(25-35). Temporal electron paramagnetic resonance (EPR) spectroscopy results show that synthetic Aβ(25-35) forms free radicals rapidly after solubilization with a high signal intensity at initial time points. At those time points, neuronal toxicity and oxidative stress gradually increase as assessed by reduction of 3-[4,5-dimethylthiazol-2-yl)-2,5-diphenyl] tetrazolium bromide, trypan blue exclusion, formation of reactive oxygen species, and detection of protein carbonyl levels. The latter occurs before neurotoxicity. When the EPR signal intensity of Aβ solution decreases at later time points, neuronal toxicity levels off and remains the same until the end of the experiment. The oxidative-sensitive enzyme creatine kinase (CK) (brain isoform) (CK-BB) content increases at initial points of the Aβ treatment in correlation with the EPR signal to keep the CK activity constant, presumably to overcome the Aβ-induced oxidative insult. CK-BB content returns to normal levels by the end of the experiment. CK activity normalized to CK content implies the presence of inactivated CK molecules during the treatment. Both Mn SOD and Cu/Zn superoxide dismutase (SOD) mRNA levels show robust increases initially, which later return to control level with decreasing oxidative insult. These results are consistent with the notion that Aβ(25-35) promotes a rapid free- radical oxidative stress to neurons, which respond by modulating various oxidative stress-handling genes.

Original languageEnglish
Pages (from-to)183-197
Number of pages15
JournalJournal of Molecular Neuroscience
Issue number3
StatePublished - 1998

Bibliographical note

Funding Information:
This work was supported in part by grants from the National Institutes of Health (AG-10836; AG-05119) and by a grant from Abercrombie Foundation. The authors gratefully acknowledge Dr. Mark Mattson for the use of the confocal laser scanning microscope and Dr. Anna Bruce-Keller for assistance with the ROS detection.


  • Amyloid β-peptide
  • Creatine kinase
  • Free radical
  • Oxidative stress
  • Protein carbonyl

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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