17 β-Estradiol alleviates synergistic oxidative stress resulting from folate deprivation and amyloid-β treatment

Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-beta (A beta) induces oxidative damage, which is likely to be compounded by deficiencies in endogenous antioxidant capacity. Indeed, folate deprivation, which has been associated with AD, potentiates generation of reactive oxygen species (ROS) by A beta. We examined whether the antioxidant 17-beta-estradiol could attenuate ROS generation following A beta treatment in the presence and absence of folate using differentiated SH-SY-5Y human neuroblastoma cells. Folate-deprivation and A beta treatment each induced an increase in ROS, and treatment of folate-deprived cultures with A beta induced a synergistic increase in ROS. 17-beta-estradiol reduced ROS levels in A beta-treated, folate-deprived cultures to ROS levels observed in cultures treated with A beta in the presence of folate, suggesting that this antioxidant was able to prevent the synergistic impact of A beta and folate deprivation on ROS generation. 17-beta-estradiol also completely prevented neuronal death induced by both A beta and folate deprivation individually, and reduced neuronal death following A beta treatment along with folate deprivation. These findings suggest that therapeutic approaches utilizing antioxidants may be particularly important in conditions such as AD, where multiple factors, including compromises in endogenous antioxidants, promote oxidative stress.