Oxidative Stress, Amyloid-beta Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer's Disease

Oxidative stress is implicated in the pathogenesis and progression of Alzheimer's disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-beta peptide, A beta(1-42) oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in A beta(1-42), but not in A beta(1-42)-poor regions, and was among the first to demonstrate A beta peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This Quadrilateral of Neuronal Death includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to A beta(1-42) and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.