AbstractOxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta‐peptide (Aβ). This 42‐mer peptide is derived from the β‐amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS‐1 and APP genes, which increase production of the highly amyloidogenic amyloid β‐peptide (Aβ42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock‐in mice expressing mutant human PS‐1 and APP were compared with those from wild‐type mice, in the presence or absence of various oxidizing agents, viz, Aβ(1–42), H2O2 and kainic acid (KA). APP/PS‐1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3‐nitrotyrosine when compared with the wild‐type neurons (p < 0.0005). Elevated levels of human APP, PS‐1 and Aβ(1–42) were found in APP/PS‐1 cultures compared with wild‐type neurons. APP/PS‐1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Aβ(1–42), H2O2 and KA compared with wild‐type neuronal cultures. The results are consonant with the hypothesis that Aβ(1–42)‐associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.