OXIDATIVE STRESS IN THE PRODUCTION AND EXPRESSION OF NEUROTOXIC BETA-AMYLOID

Although there is not yet any in vivo evidence of the neurotoxic actio n of beta-amyloid in humans, it is well established that the insoluble form of full length beta-amyloid 1-40, and the fragment comprised of amino acids 25-35, are both toxic in vitro to neurons in tissue cultur e. beta-amyloid 25-35 increases cytosolic calcium in rat PC12 cells an d 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 t he lazaroid anti-oxidant drugs, and by Vitamin E. Similarly, the neuro toxic actions of beta-amyloid 25-35 are also prevented by U-83836E and by vitamin E. These observations indicate that the actions of beta-am yloid 25-35 are mediated by free radicals. In vivo, beta-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 n eurotoxic beta-amyloid, the precursor protein must be cleaved within t he transmembrane portion of its structure. In spite of extensive world -wide effort, an enzyme capable of doing this has not been found. Howe ver, a peroxidation cascade propagated through the lipid bilayer of th e cellular membrane would cleave the precursor protein at a site neede d to form beta-amyloid. If this is the case, then free radicals would play a role both in the formation of beta-amyloid and in its neurotoxi c actions.