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 (Abeta), as the main neuropathologic marker of the disorder. It has been demonstrated that Abeta has neurotoxic properties and that such effects are mediated by free-radicals. Exposure of neuronal cells to Abeta results in a spectrum of oxidative lesions that are profoundly harmful to neuronal homeostasis. We had previously shown that Abeta25-35 induces oxidative damage to mitochondrial DNA (mtDNA) and that this modality of injury is prevented by melatonin. Because Abeta25 35 does not occur in AD and because the mode of toxicity by Abeta25-35 may be different from that of Abeta1-42 (the physiologically relevant form of Abeta), we extended our initial observations to determine whether oxidative damage to mtDNA could also be induced by Abeta1-42 and whether this type of injury is prevented by melatonin. Exposure of human neuroblastoma cells to Abeta1-42 resulted in marked oxidative damage to mtDNA as determined by a quantitative polymerase chain reaction method. Addition of melatonin to cell cultures along with Abeta completely prevented the damage. This study supports previous findings with Abeta25-35, including a causative role for Abeta in the mitochondrial oxidative lesions present in AD brains. Most important, the data confirms the neuroprotective role of melatonin in Abeta-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.
Pappolla
M A
MA
University of South Alabama Medical Center, Department of Pathology and Neurology, Mobile 36617, USA. mpappoll@usamail.usouthal.edu
Chyan
Y J
YJ
Poeggeler
B
B
Bozner
P
P
Ghiso
J
J
LeDoux
S P
SP
Wilson
G L
GL
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D018384:Oxidative Stress
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D017931:DNA Primers; D004272:DNA, Mitochondrial; D008550:Melatonin