Cyclic O₃ exposure synergizes with aging leading to memory impairment in male APOE ε3, but not APOE ε4, targeted...

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O₃) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O₃ exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O₃ exposure synergizes with the genetic risk factor APOE ε4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O₃ via working environments and few studies have addressed APOE ε4 effects on males. Surprisingly, our results show that O₃ exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O₃ exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development.