Exercise modulates APOE expression in brain cortex of female APOE3 and APOE4 targeted replacement mice

Abstract

Apolipoprotein E (ApoE) is the main cholesterol carrier of the brain and the ε4 gene variant (APOE4) is the most prevalent genetic risk factor for Alzheimer's disease (AD), increasing risk up to 15-fold. Several studies indicate that APOE4 modulates critical factors for neuronal function, including brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Both proteins show exercise-induced upregulation, which is presumed to mediate many of the beneficial effects of physical activity including improved cognition; however, there is variability in results between individuals potentially in-part due to genetic variations including APOE isoform. This study aimed to determine if the two most prevalent human APOE isoforms influence adaptive responses to exercise-training. Targeted replacement mice, homozygous for either APOE3 or APOE4 were randomized into exercised and sedentary groups. Baseline locomotor function and voluntary wheel-running behavior was reduced in APOE4 mice. Exercised groups were subjected to daily treadmill running for 8 weeks. ApoE protein in brain cortex was significantly increased by exercise in both genotypes. PGC-1α mRNA levels in brain cortex were significantly lower in APOE4 mice, and only tended to increase with exercise in both genotypes. Hippocampal BDNF protein were similar between genotypes and was not significantly modulated by treadmill running. Behavioral and biochemical variations between APOE3 and APOE4 mice likely contribute to the differential risk for neurological and vascular diseases and the exercise-induced increase in ApoE levels suggests an added feature of the potential efficacy of physical activity as a preventative and therapeutic strategy for neurogenerative processes in both genotypes.

Keywords: Apolipoprotein E (APOE); BDNF; Brain cortex; Exercise; PGC-1α.

Figure 1.. Body Weight Female APOE3 and APOE4 Mice

(A) Baseline body weight of 6-month-old APOE3 and APOE4 female mice (n=14 for APOE3, n=16 for APOE4, *p=0.0003). (B) Final body weight, of mice measured after the 8-week treadmill running regimen (n=7–8 per group, *p = 0.011, APOE3 vs. APOE4). Error bar = ± standard error of mean (SEM), SED = sedentary group, EX = exercised group

Figure 2.. Motor Activity Female APOE3 and APOE4 Mice.

(A) Timeline of locomotor procedures (B) Locomotor performance on rotarod apparatus as denoted by latency to fall. (* p= 0.001 vs. APOE3 trial 1; # p=0.027 vs. APOE3 trial 3; n=14 for APOE3, n=16 for APOE4) (C) Averaged daily voluntary wheel-running activity in APOE3 and APOE4 mice during the 7-day period, shown in 6-hr intervals. Inserted graph shows averaged total wheel turns during the 7-day period (*p= 0.037). Error bars = ± SEM.

Figure 2.. Motor Activity Female APOE3 and APOE4 Mice.

(A) Timeline of locomotor procedures (B) Locomotor performance on rotarod apparatus as denoted by latency to fall. (* p= 0.001 vs. APOE3 trial 1; # p=0.027 vs. APOE3 trial 3; n=14 for APOE3, n=16 for APOE4) (C) Averaged daily voluntary wheel-running activity in APOE3 and APOE4 mice during the 7-day period, shown in 6-hr intervals. Inserted graph shows averaged total wheel turns during the 7-day period (*p= 0.037). Error bars = ± SEM.

Figure 3.. Gene Expression of APOE, BDNF and PGC-1α in Brain Cortical Tissue of Female APOE3 and APOE4 mice.

(A) APOE protein levels in whole cortex brain tissue (*= significantly different from SED, p= 0.005) (B) BDNF protein in hippocampal tissue (C) PGC-1α mRNA in brain cortex (*= Significantly different by genotype, p = 0.002). (n=5–8 per group)

Figure 3.. Gene Expression of APOE, BDNF and PGC-1α in Brain Cortical Tissue of Female APOE3 and APOE4 mice.

(A) APOE protein levels in whole cortex brain tissue (*= significantly different from SED, p= 0.005) (B) BDNF protein in hippocampal tissue (C) PGC-1α mRNA in brain cortex (*= Significantly different by genotype, p = 0.002). (n=5–8 per group)