The Role of Oxidative Stress in Alzheimer Disease

Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. In the neurodegenerative diseases, oxidative stress has been implicated in amyotrophic lateral sclerosis, Parkinson disease, Huntington disease, and Alzheimer disease (AD). The neurodegenerative disorder receiving the most attention has been AD, in which an increase occurs in oxidation of brain lipids, carbohydrates, proteins, and DNA. Some of the products of oxidation have been found in the major histopathologic alterations in AD: the neurofibrillary tangles (NFTs) and senile plaques (reviewed in Markesbery and Carney 1 and Ceballos-Picot 2 ). These oxidative modifications are closely associated with a subtle inflammatory process in the brain in AD. Oxidative stress refers to a state in which free radicals and their products are in excess of antioxidant defense mechanisms. This imbalance can occur as a result of increased free radical production or a decrease in antioxidant defenses. Free radicals are defined as any atom or molecule that has one or more unpaired electrons in its outer shell. The reduction of molecular oxygen to water is a major source of potent radicals. The initial step in this reaction yields the superoxide radical, which produces hydrogen peroxide by addition of an electron. The reduction of hydrogen peroxide yields the highly reactive hydroxyl radical. These radicals plus singlet oxygen are called reactive oxygen species (ROS). Several reactive nitrogen species, nitric oxide, and peroxynitrite also are important modulators of oxidative stress. These free radicals and others are capable of reacting with lipids, proteins, nucleic acids, and other molecules and altering their structure and function. Oxidative stress can lead to alterations in cells with an accumulation of oxidized products such as aldehydes and isoprostanes from lipid peroxidation, protein carbonyls from protein oxidation, and base ad