Interactions Between Gene, Environment, and Aging in Modulation of Brain Redox Potential and Memory

The cause for the late-onset (sporadic) Alzheimer’s disease (AD), which accounts for 95% of AD cases, is unknown and most likely conferred by complex interactions between genetic and environmental risk factors plus aging. How the genetic and environmental risk factors as well as aging interact, leading to AD, however, is unknown. In this study, we explored the potential interactions between ApoE4, a genetic risk factor, O3, an environmental risk factor, and aging in the induction of memory impairment, using human ApoE4 and ApoE3 (the majority of human population carry the ApoE3 gene) targeted replacement (TR) male mice. The results show that exposure to O3 following a cyclic exposure protocol, which mimics human exposure scenarios, impairs memory of old ApoE3 TR mice, although it has no significant effect on the memory of young ApoE3 and ApoE4 or old ApoE4 TR mice. The concentrations of glutathione (GSH), an important antioxidant, decrease with age and with O3 exposure in frontal cortex (FC) and hippocampus, two brain areas affected mainly in AD, in ApoE3 TR mice, but only in FC of ApoE4 TR mice. The GSH and GSSG redox potentials decrease with age in the FC and hippocampus of ApoE3, but not ApoE4, TR mice; O3 exposure, on the other hand, reduces the redox potential in young ApoE3 and old ApoE4 TR mice. Cysteine concentrations decrease with age and with O3 exposure in both FC and hippocampus in ApoE3, but not in ApoE4, TR mice. The cysteine/cystine redox potentials, a major extracellular redox couple, decrease with O3 exposure in both brain areas in young and old ApoE3 TR mice, but only in the frontal cortex of young ApoE4 TR mice. Together, the results suggest that male ApoE3 TR mice are more sensitive to aging- and O3-induced oxidative stress than ApoE4 TR mice, although young ApoE4 mice per se experience increased level of oxidative stress, compared to young ApoE3 TR mice. The results also suggest that increased sensitivity to oxidative stress may underlie memory loss in O3 exposed old ApoE3 TR mice. As ApoE4 mainly affects females, interactions between ApoE4, O3, and aging in modulation of brain oxidative stress levels and memory in females warrant further investigation.