P4‐170: Peroxidative nitrotyrosine formation in Alzheimer's disease

Findings from numerous approaches in Alzheimer disease (AD) implicate oxidative stress as a major pathogenic pathway. We have focused our studies to elucidate the nature of the reactive species and sources of oxidative insult by considering cellular biomacromolecule modifications such as carbonyl and nitrotyrosine formation. These studies have strongly implicated metal catalyzed oxidation as critical to oxidative damage in AD. This led us to re-examine our prior work implicating non-metal catalyzed oxidation through peroxynitrite. In this study, we examine whether peroxynitrite or peroxidative nitration with nitrite and hydrogen peroxide is responsible for tyrosine nitration. We found that peroxidative nitration yields nitrotyrosine in tissue with the characteristic cytoplasmic and nuclear distribution found in AD. Significantly, the process is dependent on redox active transition metals. In contrast, peroxynitrite produced less-widespread damage without the anatomic signature of AD. This study suggests nitration of proteins in neurons in AD is in fact dependent on site directed metal-catalyzed processes, further evidence for the significant role of metals in the process of neurodegeneration. It is our conclusion that a reaction involving nitrite, hydrogen peroxide and the redox active metals shown to be elevated in AD, may play the primary roles of oxidative nitrotyrosine damage in AD. To truly target the in vivo mechanisms occurring in neurons in the brain, a complete picture of all nitrative events and consequences must be known. At the least, increasing awareness of the multiple possible pathways leading to the endpoints classified as nitrative damage will only increase the chances for therapeutic success.