Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro

DOWN'S syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation 1 . Development of the DS brain is associated with decreased neuronal number and abnormal neuronal differentiation 2–7 , and adults with DS develop Alzheimer's disease 8,9 . The cause of the neurodegenerative process in DS is unknown. Here we report that cortical neurons from fetal DS and age-matched normal brain differentiate normally in culture, but DS neurons subsequently degenerate and undergo apoptosis whereas normal neurons remain viable. Degeneration of DS neurons is prevented by treatment with free-radical scavengers or catalase. Furthermore, DS neurons exhibit a three- to fourfold increase in intracellular reactive oxygen species and elevated levels of lipid peroxidation that precede neuronal death. These results suggest that DS neurons have a defect in the metabolism of reactive oxygen species that causes neuronal apoptosis. This defect may contribute to mental retardation early in life and predispose to Alzheimer's disease in adults.