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

Most contemporary progress in Alzheimer's disease (AD) stems from the study of a 42-43 amino acid peptide, called the amyloid beta protein (A beta), a s the main neuropathololgic marker of the disorder, It has been demonstrate d that A beta has neurotoxic properties and that such effects are mediated by free-radicals, Exposure of neuronal cells to A beta results in a spectru m of oxidative lesions that are profoundly harmful to neuronal homeostasis. We had previously shown that. A beta 25-35 induces oxidative damage to mit ochondrial DNA (mtDNA) and that this, modality of injury is prevented by me latonin. Because A beta 25-35 does not occur in AD and because the mode of toxicity by A beta 25-35 may be different from that of A beta 1-42 (the phy siologically relevant form of A beta), we extended our initial observations to determine whether oxidative damage to mtDNA could also be induced by A beta 1-42 and whether this type of injury is prevented by melatonin. Exposu re of human neuroblastoma cells to A beta 1-42 resulted in marked oxidative damage to mtDNA as determined by a quantitative polymerase chain reaction method. Addition of melatonin to cell cultures along with A beta completely prevented the damage. This study supports previous findings with A beta 25 -35, including a causative role for A beta in the mitochondrial oxidative: lesions present in AD brains. Most important, the data confirms the neuropr otective role of melatonin in A beta-mediated oxidative injury. Because mel atonin also inhibits amyloid aggregation, lacks toxicity, and efficiently c rosses the blood-brain barrier, this hormone appears superior to other avai lable antioxidants as a candidate for pharmacologic intervention in AD.