Alzheimer β protein mediated oxidative damage of mitochondrial DNA: Prevention by melatonin

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Abstract
Most contemporary progress in Alzheimer's disease (AD) stems from the study of a 42–43 amino acid peptide, called the amyloid beta protein (Aβ), as the main neuropathologic marker of the disorder. It has been demonstrated that Aβ has neurotoxic properties and that such effects are mediated by free-radicals. Exposure of neuronal cells to Aβ results in a spectrum of oxidative lesions that are profoundly harmful to neuronal homeostasis. We had previously shown that Aβ25 35 induces oxidative damage to mitochondrial DNA (mtDNA) and that this modality of injury is prevented by melatonin. Because Aβ25-35 does not occur in AD and because the mode of toxicity by Aβ25-35 may be different from that of Aβ1-42 (the physiologically relevant form of Aβ), we extended our initial observations to determine whether oxidative damage to mtDNA could also be induced by Aβ1-42 and whether this type of injury is prevented by melatonin. Exposure of human neuroblastoma cells to Aβ1-42 resulted in marked oxidative damage to mtDNA as determined by a quantitative polymerase chain reaction method. Addition of melatonin to cell cultures along with Aβ completely prevented the damage. This study supports previous findings with Aβ25-35, including a causative role for Aβ in the mitochondrial oxidative lesions present in AD brains. Most important, the data confirms the neuroprotective role of melatonin in Aβ-mediated oxidative injury. Because melatonin also inhibits amyloid aggregation, lacks toxicity, and efficiently crosses the blood-brain barrier, this hormone appears superior to other available antioxidants as a candidate for pharmacologic intervention in AD.