Amyloid β peptides (Aβ) may be neurotoxic during the progression of Alzheimer’s disease by eliciting oxidative stress. Exposure of neuronally differentiated SK-N-BE cells to Aβ_25–35 fragment as well as to full-length Aβ_1–40 and Aβ_1–42 induces early and time-dependent generation of oxidative stress that has been evaluated by carefully monitoring generation of hydrogen peroxide (H₂O₂), 4-hydroxynonenal (HNE), thiobarbituric acid reactive substances (TBARS), and fluorescent chromolipids. Aβ treatment also results in the activation of c-Jun aminoterminal kinases (JNKs) and p38^MAPK and is followed by characteristic nuclear changes of apoptosis as evaluated by DAPI staining and TUNEL technique. To reproduce the relationships between oxidative stress and Aβ apoptosis we found that only the simultaneous administration of HNE and H₂O₂, at concentrations similar to those generated within the first 3 h of Aβ exposure, can fully mimic Aβ-dependent activation of JNKs and p38^MAPK and occurrence of apoptosis. Antioxidants such as α-tocopherol and N-acetylcysteine prevent completely either neuronal apoptosis or activation of JNKs and p38^MAPK elicited by Aβ or by simultaneous HNE and H₂O₂ addition. Finally, direct evidence that activation of these kinases is required for cell death induced by Aβ has been obtained by pretreating cell with specific inhibitors of JNKs and p38^MAPK. These results suggest the existence of a sequence of events in Aβ-induced apoptosis involving simultaneous generation of HNE and H₂O₂ and oxidative stress-dependent activation of JNKs and p38^MAPK.