Oxidative stress in the production and expression of neurotoxic β-amyloid

Abstract

Although there is not yet any in vivo evidence of the neurotoxic action of β-amyloid in humans, it is well established that the insoluble form of full length β-amyloid 1–40, and the fragment comprised of amino acids 25–35, are both toxic in vitro to neurons in tissue culture. β-amyloid 25–35 increases cytosolic calcium in rat PC12 cells and in rat cortical neurons in primary culture by facilitating the entry of extracellular calcium into the cell. This effect is not altered by calcium channel blocking drugs but is prevented by U-83836E, one of the lazaroid anti-oxidant drugs, and by vitamin E. Similarly, the neurotoxic actions of β-amyloid 25–35 are also prevented by U-83836E and by vitamin E. These observations indicate that the actions of β-amyloid 25–35 are mediated by free radicals. In vivo, β-amyloid 1–40 is cleaved from a precursor protein that appears to be synthesized and inserted into cellular membranes following damage to cells. To form neurotoxic β -amyloid, the precursor protein must be cleaved within the transmembrane portion of its structure. In spite of extensive world-wide effort, an enzyme capable of doing this has not been found. However, a peroxidation cascade propagated through the lipid bilayer of the cellular membrane would cleave the precursor protein at a site needed to form β-amyloid. If this is the case, then free radicals would play a role both in the formation of β-amyloid and in its neurotoxic actions.