INTERACTION OF APOE GENOTYPE, ANTIOXIDANTS AND EXERCISE ON BRAIN FUNCTION.

Huge rise in the incidence of azheimer's disease is projected with baby boomers' retiring age. There are very few drugs in market to manage this condition. Doctors and care takers often depend on the lifestyle modification to assist the definitive drug therapy. Most common form of lifestyle modification is exercise and diet rich in antioxidants. Further, APOE4 is a gene that is commonly expressed and a well established genetic risk factor for Alzheimer's development. We identified role of gender and APOE4 in affecting the benefits of lifestyle modification. We used a mouse model that express human APOE4 and develops memory loss at early age. This model is routinely used for alzheimer's disease related experiments. We treated these mice with treadmill based exercise and fed them with diet rich in antioxidants like vitamin C and vitamin E. After treatment these mice were tested for learning and memory abilities using interesting and non stressful techniques that involve swimming, running on rotating rod etc. We found that exercise and antioxidants are more beneficial in combination in only some of the tests. The benefits of the combination of exercise and antioxidants depends on sex, APOE genotype and age of the mouse. Purpose (a): The ε4 allele of apolipoprotein E (ApoE) has been associated with increased risk for the development of late-onset Alzheimer’s disease (AD). To prevent or reduce the appearance of brain dysfunction, a healthy lifestyle, such as exercising and eating antioxidants, is often recommended. Physical activity has been shown to have an allele-specific beneficial effect on cognition in humans and rodents. Antioxidant therapy is often suggested to improve brain function, as increased oxidative stress has been correlated with brain dysfunction, especially in ε4 carriers. Health conscious individuals are likely to combine exercise with antioxidant intake to increase protection; however recent studies have indicated a potential negative interaction of these two factors. In some cases, antioxidant intake abolished the beneficial effects of exercise. Our study aimed at determining the nature of the interaction between exercise and antioxidants on functional outcomes in a model of increased AD risk. Methods (b): Male and female mice (12month), expressing the human ApoE3 or E4, were placed under one of the treatment: Sedentary/control diet (SedCon), Sedentary /antioxidant-rich diet (Vitamins E-195mg/kg body weight/day and C-287mg/kg body weight/day; SedEC), Exercise/control diet (ExCon), Exercise/ antioxidant-rich diet (ExEC), for 8 weeks prior to behavioral testing including coordinated running (rotorod), spatial learning and memory (Morris water maze) and discriminated avoidance (T-maze). Results (c): Overall, ApoE3 mice performed better than ApoE4 mice on the rotorod test and ExEC treatment improved the performance of the male ApoE3 only. The ExEC treatment improved spatial learning in both male and female ApoE4 mice, whereas ExCon improved performance only in the ApoE4 females. Maximum spatial learning was improved with ExEC in males regardless of genotype but only in the ApoE3 females. In the discriminated avoidance task, initial learning was improved with ExCon treatment in ApoE3 mice regardless of gender. Cognitive flexibility was improved by ExEC treatment in ApoE3 male and female and in ApoE4 females but not in male ApoE4. Conclusions (d): These results indicate that genotype and sex are critical determinants in the functional outcomes of the treatment regimens.