title: The role of intracellular zinc release in aging, oxidative stress, and Alzheimer's disease.
abstract: Brain aging is marked by structural, chemical, and genetic changes leading to cognitive decline and impaired neural functioning. Further, aging itself is also a risk factor for a number of neurodegenerative disorders, most notably Alzheimer's disease (AD). Many of the pathological changes associated with aging and aging-related disorders have been attributed in part to increased and unregulated production of reactive oxygen species (ROS) in the brain. ROS are produced as a physiological byproduct of various cellular processes, and are normally detoxified by enzymes and antioxidants to help maintain neuronal homeostasis. However, cellular injury can cause excessive ROS production, triggering a state of oxidative stress that can lead to neuronal cell death. ROS and intracellular zinc are intimately related, as ROS production can lead to oxidation of proteins that normally bind the metal, thereby causing the liberation of zinc in cytoplasmic compartments. Similarly, not only can zinc impair mitochondrial function, leading to excess ROS production, but it can also activate a variety of extra-mitochondrial ROS-generating signaling cascades. As such, numerous accounts of oxidative neuronal injury by ROS-producing sources appear to also require zinc. We suggest that zinc deregulation is a common, perhaps ubiquitous component of injurious oxidative processes in neurons. This review summarizes current findings on zinc dyshomeostasis-driven signaling cascades in oxidative stress and age-related neurodegeneration, with a focus on AD, in order to highlight the critical role of the intracellular liberation of the metal during oxidative neuronal injury.
authors.affiliation: Department of Neurobiology, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: McCord
authors.affiliation: Department of Neurobiology, University of Pittsburgh School of Medicine Pittsburgh, PA, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
keywords: Alzheimer’s disease; aging; apoptosis; autophagy; oxidative stress; zinc