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

The polyamines, relatively low-molecular-weight aliphatic compounds, are th e main inducers of eukaryotic cell growth and proliferation. Although polya mine requirements for cell growth are well defined, their role is still eni gmatic. We have previously reported that amyloid beta -peptide (A beta), th e main constituent of senile plaques in Alzheimer's disease (AD) brain, is toxic to neurons through a free radical-dependent oxidative stress mechanis m 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 up take and increased ornithine decarboxylase (ODC) activity. Both effects wer e prevented by the free radical scavenger vitamin E. Spermine has been repo rted to function directly as a free radical scavenger. In the current study , we aimed to address whether up-regulation of polyamine metabolism is a de fense against, or a result of, A beta -induced oxidative stress by investig ating the capability of spermine to quench A beta -associated free radicals in solution and to assert a protective function of spermine in neuronal cu lture 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 difluoromethylounithine (DFMO) did not protect cells from A beta -induced f ree radical toxicity, and stimulation of the synthesis of putrescine and sp ermine by the aminopropyltransferase inhibitor S-adenosyl-1,8- diamino-thio octane (AdoDATO), rather, further enhanced A beta -induced toxicity. Althou gh spermine is capable of scavenging free radicals generated by A beta in s olution as measured by electron paramagnetic resonance (EPR) spectroscopy, the up-regulated transport of exogenously added spermine together with A be ta may lead to overaccumulation of a cellular spermine pool, with resulting enhanced neurotoxicity. (C) 2001 Wiley-Liss, Inc.