Role of spermine in amyloid β-peptide-associated free radical-induced neurotoxicity

Servet M. Yatin, Mustafa Yatin, Sridhar Varadarajan, Kenneth B. Ain, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


The polyamines, relatively low-molecular-weight aliphatic compounds, are the main inducers of eukaryotic cell growth and proliferation. Although polyamine requirements for cell growth are well defined, their role is still enigmatic. We have previously reported that amyloid β-peptide (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD) brain, is toxic to neurons through a free radical-dependent oxidative stress mechanism and that Aβ(1-42), the principal form of Aβ in AD brain, causes an increase in polyamine metabolism manifested by up-regulated polyamine uptake and increased ornithine decarboxylase (ODC) activity. Both effects were prevented by the free radical scavenger vitamin E. Spermine has been reported to function directly as a free radical scavenger. In the current study, we aimed to address whether up-regulation of polyamine metabolism is a defense against, or a result of, Aβ-induced oxidative stress by investigating the capability of spermine to quench Aβ-associated free radicals in solution and to assert a protective function of spermine in neuronal culture against Aβ. Pretreatment of cultured neurons with spermine prior to Aβ exposure failed to prevent Aβ-induced cell death. Indeed, Aβ plus spermine added to cultured neurons was even more neurotoxic than either agent alone. Additionally, inhibition of the polyamine synthesis by difluoromethylornithine (DFMO) did not protect cells from Aβ-induced free radical toxicity, and stimulation of the synthesis of putrescine and spermine by the aminopropyltransferase inhibitor S-adenosyl-1,8diamino-thiooctane (AdoDATO), rather, further enhanced Aβ-induced toxicity. Although spermine is capable of scavenging free radicals generated by Aβ in solution as measured by electron paramagnetic resonance (EPR) spectroscopy, the up-regulated transport of exogenously added spermine together with Aβ may lead to overaccumulation of a cellular spermine pool, with resulting enhanced neurotoxicity.

Original languageEnglish
Pages (from-to)395-401
Number of pages7
JournalJournal of Neuroscience Research
Issue number5
StatePublished - Mar 1 2001


  • Alzheimer's disease
  • Electron paramagnetic resonance
  • Ornithine decarboxylase
  • Oxidation
  • Polyamine

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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