Free radicals in the neurotoxic actions of beta-amyloid.

The fragment of the beta-amyloid protein that contains the peptide sequence 25 to 35 of the parent compound, increases cytosolic calcium and is directly cytotoxic to neurons in tissue culture. The cytotoxic action of beta-amyloid has been considered to be the primary determinant of the neurodegeneration observed in Alzheimer's disease. The cytotoxic effects of beta-amyloid 25-35 or beta-amyloid 1-40 added to primary cultures of rat hippocampal or cortical neurons can be reduced or prevented by anti-oxidant lazaroid drugs such as U-74500A, U-78517F, or U-83836E. beta-amyloid 25-35 evokes an immediate increase in cytosolic calcium when added to suspensions of PC 12 cells, and is cytotoxic to PC 12 cells in tissue culture. Both the calcium-elevating and the cytotoxic actions of beta-amyloid 25-35 on PC 12 cells are reduced or prevented by lazaroid anti-oxidant drugs. Since the lazaroids have been shown to scavenge free radical species, the present results indicate that the actions of beta-amyloid 25-35 on calcium regulation and on cell survival are mediated by free radicals.