Cyclic ozone exposure synergizes with aging leading to memory impairment in male apoE3, not apoE4, targeted replacement mice

The etiology of Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is unknown. Recent epidemiology studies suggest that exposure to unhealthy levels of ozone (O 3 ), a highly reactive oxidant and one of most abundant urban pollutant, may be responsible. Whether O 3 acts alone or synergizes with other risk factors, such as aging and APOEe4, leading to AD remains to be determined. To test whether O 3 exposure, APOEe4, and aging negatively interact leading to AD, we exposed otherwise healthy male apoE4 targeted replacement (TR) mice to a cyclic O 3 exposure protocol, which mimics human exposure scenarios, and compared the results to male apoE3 TR mice, which represent the majority of the human population who carries the APOE e3 gene. The results show, surprisingly, that O 3 exposure impairs memory of old male apoE3, but not apoE4, mice nor young apoE3 or apoE4 mice. Further studies show that glutathione concentration decreases with increased age and with O 3 exposure in the hippocampus of male apoE3 mice, although its concentration is low in male apE4 mice since young age. Cysteine concentration, on the other hand, increases with age in apoE4 mice. The activities of several antioxidant enzymes including thioredoxin 1 are also increased in the hippocampus of old apoE4 mice, compared to old apoE3 mice. This is associated with diminished lipid and protein oxidation, astrocyte activation/inflammation, and neurogenesis in O 3 exposed old apoE4 mice. Our results show, for the first time, that APOEe4, a genetic risk factor for AD, actually protects old male mice from O 3 -induced memory impairment, probably because old apoE4 male mice have developed compensatory mechanisms to combat O 3 -induced oxidative stress