Oxidative stress impairs learning and memory in apoE knockout mice

Cardiovascular risk factors, such as oxidative stress and elevated lipids, are linked to the development of cognitive impairment. A mediator common to both stressors is the apolipoprotein E (apoE). The objectives of this study are to determine the effects of apoE deficiency and diet-induced systemic oxidative stress in mice on vascular expression of inflammatory proteins and on cognitive function. Mice are placed on a diet enriched in homocysteine for fifteen weeks and then assessed for spatial learning using an eight-arm radial maze and for inflammatory protein expression by immunohistochemistry. Our results show that diet-induced oxidative stress does not affect cognitive function in normal mice. In contrast, apoE-/- mice on the homocysteine diet show significantly impaired (p<0.001) maze performance. ApoE-/- mice also have high cholesterol levels. There is no expression of inflammatory proteins IL-6 and IL-8 in the vasculature of control mice on normal or homocysteine diet and little in apoE-/- mice on normal diet. In contrast, apoE-/- mice on homocysteine diet show pronounced vascular reactivity to IL-6 and IL-8 antibodies. These data show that systemic oxidative stress correlates with expression of inflammatory proteins in the cerebral vasculature and impaired cognitive function. These results are consistent with the hypothesis that an oxidative-inflammatory cycle in the cerebral vasculature could have deleterious consequences for cognition.