Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease.

Elevated production of amyloid-beta (A beta) as a preventive antioxidant for brain lipoproteins under the action of increased oxidative stress in aging is postulated to represent a major event in the development of Alzheimer's disease (AD). Increase in A beta production is followed by chelation of transition metal ions by A beta, accumulation of A beta-metal lipoprotein aggregates, production of reactive oxygen species and neurotoxicity. Chelation of copper by A beta is proposed to be a most important part of this pathway, because A beta binds copper stronger than other transition metals and because copper is a more efficient catalyst of oxidation than other metals. This amyloid-binds-copper (ABC) model does not remove A beta peptide from its central place in our current thinking of AD, but rather places additional factors in the center of discussion. Most importantly, they embrace pathological mechanisms known to develop in aging (which is the major risk factor for AD), such as increased production of reactive oxygen species by mitochondria, that are positioned upstream relative to the generation of A beta.