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

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 beta-peptide (A beta), 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 A beta(1--42), the principal form of A beta 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, A beta-induced oxidative stress by investigating the capability of spermine to quench A beta-associated free radicals in solution and to assert a protective function of spermine in neuronal culture against A beta. Pretreatment of cultured neurons with spermine prior to A beta exposure failed to prevent A beta-induced cell death. Indeed, A beta 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 A beta-induced free radical toxicity, and stimulation of the synthesis of putrescine and spermine by the aminopropyltransferase inhibitor S-adenosyl-1,8-diamino-thiooctane (AdoDATO), rather, further enhanced A beta-induced toxicity. Although spermine is capable of scavenging free radicals generated by A beta in solution as measured by electron paramagnetic resonance (EPR) spectroscopy, the up-regulated transport of exogenously added spermine together with A beta may lead to overaccumulation of a cellular spermine pool, with resulting enhanced neurotoxicity.