The amyloid paradox: amyloid-beta-metal complexes can be neurotoxic and neuroprotective

Senile plaques in the brains of people with Alzheimer disease (AD) are primarily composed of the amyloid-beta (Abeta) peptide and contain substantially elevated levels of iron, copper and zinc. These metals bind to Abeta and have been reported to increase the toxicity of Abeta to cultured neurones. Other reports have demonstrated that Abeta can reduce the neurotoxicity of metal ions, suggesting that the interaction can, under some circumstances, be protective. To investigate these apparently conflicting results, human Abeta1-42 was co-injected with iron, copper or zinc (at the concentrations found in plaques) into rat cerebral cortex, and the resulting numbers of dying neurones were compared. It was found that Abeta complexed with either iron or zinc was more toxic than Abeta alone. In contrast, Abeta-copper complexes were not neurotoxic. Surprisingly, we observed that when iron or copper were combined with Abeta, the neurotoxicity of these metals was substantially reduced, suggesting that Abeta may help to limit the toxicity of redox-active metal ions, thereby assisting the antioxidant defence of the brain. Thus paradoxical effects occur when Abeta complexes with metal ions, where Abeta-metal complexes are capable of being neurotoxic and neuroprotective.