Oxidative Stress Occurs Prior to Amyloid Aβ Plaque Formation and Tau Phosphorylation in Alzheimer's Disease: Role of Glutathione and Metal Ions

Alzheimer's disease (AD) is an insidious and progressiveneurodegenerative disorder that affects millions of people worldwide.Although the pathogenesis remains obscure, there are two dominantcausal hypotheses. Since last three decades, amyloid beta (A & beta;)deposition was the most prominent hypothesis, and the other isthe tau hyperphosphorylation hypothesis. The confirmed diagnosticcriterion for AD is the presence of neurofibrillary tangles (NFTs)composed of hyperphosphorylated tau and the deposition of toxic oligomericA & beta; in the autopsied brain. Consistent with these hypotheses,oxidative stress (OS) is garnering major attention in AD research.OS results from an imbalance of pro-oxidants and antioxidants. Thereis a considerable debate in the scientific community on which processoccurs first, OS or plaque deposition/tau hyperphosphorylation. Basedon recent scientific observations of various laboratories includingours along with critical analysis of those information, we believethat OS is the early event that leads to oligomeric A & beta; depositionas well as dimerization of tau protein and its subsequent hyperphosphorylation.This OS hypothesis immediately suggests the consideration of noveltherapeutic approaches to include antioxidants involving glutathioneenrichment in the brain by supplementation with or without an ironchelator.