Perspectives on Oxidative Stress in Alzheimer's Disease and Predictions of Future Research Emphases.

Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer's disease (AD). This recognition arose in significant part from the work in the author's laboratory, complemented by research from others' laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author's laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20-30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder.