WIDESPREAD PEROXYNITRITE-MEDIATED DAMAGE IN ALZHEIMERS-DISEASE

Increasing evidence suggests that oxidative damage to proteins and oth er macromolecules is a salient feature of the pathology of Alzheimer's disease. Establishing the source of oxidants is key to understanding what role they play in the pathogenesis of Alzheimer's disease, and on e way to examine this issue is to determine which oxidants are involve d in damage. In this study, we examine whether peroxynitrite, a powerf ul oxidant produced from the reaction of superoxide with nitric oxide, is involved in Alzheimer's disease. Peroxynitrite is a source of hydr oxyl radical-like reactivity, and it directly oxidizes proteins and ot her macromolecules with resultant carbonyl formation from side-chain a nd peptide-bond cleavage. Although carbonyl formation is a major oxida tive modification induced by peroxynitrite, nitration of tyrosine resi dues is an indicator of peroxynitrite involvement. In brain tissue fro m cases of Alzheimer's disease, we found increased protein nitration i n neurons, including but certainly not restricted to those containing neurofibrillary tangles (NFTs). Conversely, nitrotyrosine was undetect able in the cerebral cortex of age-matched control brains. This distri bution is essentially identical to that of free carbonyls. These findi ngs provide strong evidence that peroxynitrite is involved in oxidativ e damage of Alzheimer's disease. Moreover, the widespread occurrence o f nitrotyrosine in neurons suggests that oxidative damage is not restr icted to long-lived polymers such as NFTs, but instead reflects a gene ralized oxidative stress that is important in disease pathogenesis.